HIV protease inhibitors

ABSTRACT

The present invention related to novel dihydropyrones possessing 3-position nitrogen atom, which inhabit the HIV aspartyl protease blocking HIV infectivity. The dihydropyrones are useful in the development of therapies for the treatment of viral infections, and diseases, including AIDS.

This application claims the benefit of Provisional Application No.60/169,754 filed Dec. 9, 1999.

BACKGROUND OF THE INVENTION

The HIV-protease enzyme is absolutely essential for the replication anddissemination of HIV throughout the body (Navia M. A. and McKeever B.M., Ann. New York Acad. Sci., 1990; 616:73-85) and has become anextremely important target for the design and development of anti-HIVtherapeutic agents (von der Helm K., Biol. Chem. 1996; 377:756-774).Several peptidomimetic HIV protease inhibitors have been successfullydeveloped (such as indinavir, saquinavir, ritonavir, and nelfinavir),which demonstrate significant clinical success in lowering plasma viralload, reducing the onset to AIDS, and decreasing the frequency ofopportunistic infections (Deeks S. G., Smith M., Holodniy M., and KahnJ. O., JAMA. 1997; 277:145-153).

Yet the current HIV protease inhibitors by their peptidomimetic naturehave relatively poor solubility, high biliary excretion, limitedbioavailabilities and significant liver metabolism. These drawbacks inturn increase the need for high doses of a drug, which increases thefrequency of various side effects and multiple drug interactions (BarryM., Gibbons S., Back D., and Mulcahy F., Clin. Pharmacokinet., 1997;32:194-209). More importantly, resistance to the current HIV proteaseinhibitors has emerged (Shock H. B., Garsky V. M., and Kuo L., J. Biol.Chem., 1996;271:31957-31963) resulting in treatment failures(Fatkenheuer G., Theisen A., Rockstroh J., Grabow T., et al., AIDS,1997;11:F113-F116). From this discussion, it is apparent that while HIVprotease is an excellent antiviral target for the treatment of HIVinfection and AIDS, there is a need to identify non-peptide inhibitorswith improved pharmacological properties and which are not crossresistant with the current drugs (Wallace R. W., DDT, 1997;2:83-84).

U.S. Pat. No. 5,789,440 recites non-peptidic HIV protease inhibitors offormula A

The patent is hereby incorporated by reference. Excellent HIV proteaseinhibition was achieved, but the antiviral activity at the cellularlevel was in some cases less than desired for an ideal therapeutic agentdue to poor overall pharmacological properties (Tummino P. J., VaraPrasad J. V. N., Ferguson D., Nauhan C., et al., BioOrganic and MedChem., 1996;4:1401-1410). These efforts however led to a core structureB where R₁ and R₂ were alkyl groups filling the

S₁′ and S₂′ pockets, respectively, and the phenyl of the phenethyl groupat C₆ filled the S₂ pocket very efficiently. This core structure wasrecognized as a valuable platform for additional study (Tait B. D.,Hagen S., Domagala J. M., Ellsworth E. L., et al., J. Med. Chem.,1997;40:3781-3792).

Additional dihydropyrones C were reported when it was unexpectedlydiscovered that certain groups which reduced lipophilicity judiciouslyplaced at R₁-R₅ led to greatly

improved antiviral cellular activity. See U.S. Pat. No. 5,834,506. Thepatent is hereby incorporated by reference. Among the preferredcompounds were those where R₁ and R₅ were OH, NH₂, or CH₂OH. In suchcases, the preferred R₄ included a small alkyl chain or ring and R₆ wasmethyl. In addition to improved cellular antiviral activity, thecompounds also showed good pharmacokinetics in animals relative to theless-polar substituted compounds. These compounds were also not crossresistant with current HIV Protease inhibitors (Hagen S. E., Vara PrasadJ. V. N., Boyer F. E., Domagala J. M ., et al., J. Med.,1997;40:3707-3711; Vander Roest S., Wold S., and Saunders J., 37^(th)Interscience Conference on Antimicrobial Agents and Chemotherapy, Sep.28-Oct. 1, 1997, Toronto, Canada. Abstract I-84; Domagala J. M., BoyerF., Ellsworth E., Gajda C., et al., 5^(th) Conference on Retrovirusesand Opportunistic Infections, Feb. 1-5, 1998, Chicago, Ill. Abstract638).

While the compounds C were notable for their improved pharmacologicalproperties relative to the non-polar substituted core molecules B, thesehighly favorable properties were conferred directly by the use of OH,NH₂ and NR₂ groups placed on the lipophilic rings. The rings themselveswere important for binding to the enzyme “pockets” and for holding thet-butyl group and the groups R₁-R₃ and R₅ in their proper places withinthe enzyme's active site.

This hereby incorporates by reference 5888L1-01-TMC filed on even dateherewith entitled “A Method of Making Dihydropyrone HIV ProteaseInhibitors” by Victor Fedij et al.

SUMMARY OF THE INVENTION

The present invention relates to compounds or pharmaceuticallyacceptable salts thereof of formula I, shown below:

wherein:

R₁ is H, a straight or branched alkyl of 1-6 carbons or a carbocycle of3-6 carbons,

R₂ is H, a straight or branched alkyl of 1-5 carbons or a carbocycle of3-6 carbons;

R₃ is H [C(R₉)₂]_(n)OR, [C(R₉)₂]_(n)N(R)₂, [C(R₉)₂]_(n)N(R₉)COR,[C(R₉)₂]_(n)CO₂R, [C(R₉)₂]_(n)(O)COR, [C(R₉)₂]_(n)CON(R)₂,[C(R₉)₂]_(n)OC(O)N(R)₂, [C(R₉)₂R], [C(R₉)₂]_(n)N(R₉)CON(R)₂,[C(R₉)₂]_(n)N(R₉)CO₂R, [C(R₉)₂]_(n)OSO₂N(R)₂, [C(R₉)₂]_(n)N(R₉)SO₂OR,[C(R₉)₂]_(n)N(R₉)SO₂N(R)₂, [C(R₉)₂]_(n)OSO₂R, [C(R₉)₂]_(n)N (R₉)SO₂R,[C(R₉)₂]_(n)SO_(p)R, [C(R₉)₂]_(n)N(R₉)CSN(R)₂,[C(R₉)₂]_(n)N(R₉)C(═NR₉)N(R)₂, [C(R₉)₂]_(n)SO₂N(R)₂,[C(R₉)₂]_(n)C(NR₉)N(R)₂, [C(R₉)₂]_(n)COR, O[C(R₉)₂]_(m)OR,N(R)[C(R₉)₂]_(m)OR, F, Cl, Br, CF₃, CN, or ═O when Ar is Het;

R₄, R₅, and R₆ are independently H, a straight or branched alkyl of 1-6carbons, a cycloalkyl of 3-6 carbons, [C(R₉)₂]_(n)OR, [C(R₉)₂]_(n)N(R)₂,F, Cl, Br, CN, CF₃, ═O when Ar is Het; [C(R₉)₂]_(n)N(R₉)COR,[C(R₉)₂]_(n)SO_(p)R, [C(R₉)₂]_(n)R, [C(R₉)₂]_(n)(O)COR, O[C(R₉)₂]_(m)OR,N(R)[C(R₉)₂]_(m)OR, [C(R₉)₂]_(n)N(R₉)CON(R)₂, [C(R₉)₂]_(n)(O)CON(R)₂,[C(R₉)₂]_(n)NR₉CO₂R, [C(R₉)₂]_(n)COR, [C(R₉)₂]_(n)CO₂R,[C(R₉)₂]_(n)CON(R)₂, [C(R₉)₂]_(n)N(R₉)SO₂R, [C(R₉)₂]_(n)SO₂N(R)₂,[C(R₉)₂]_(n)N(R₉)SO₂OR, [C(R₉)₂]_(n)OSO₂N(R)₂,[C(R₉)₂]_(n)N(R₉)SO₂N(R)₂, [C(R₉)₂]_(n)C(═NR₉)N(R)₂,[C(R₉)₂]_(n)N(R₉)C(═NR₉)N(R)₂, [C(R₉)₂]_(n)Het;

any two of R₁-R₃ or R₄-R₆ may together form a ring of 5-6 total atomswhich may contain 0-3 heteroatoms;

X is NH, NR₈;

f is an integer of from 0 to 3;

n is an integer of from 0 to 3;

m is an integer of from 2 to 4;

p is an integer from 1 to 2;

R₇ is a straight or branched alkyl of 1-6 carbons or a carbocycle of 3-6carbons;

R₈ is a straight or branched alkyl of 1-6 carbons, a carbocycle of 3-6carbons, (CH₂)_(n)Ph, or a (CH₂)_(n)heterocycle of 5-6 atoms containing1-4 heteroatoms and wherein the (R)₂ in N(R)₂ optionally forms aheterocycle containing the nitrogen, all optionally substituted by F,Ci, Br, OR₉, CN, CO₂R₉, N(R₉)₂, NR₉COR₉, CF₃, or ═O; or an alkyl groupbearing polar functionalities, optionally including OH, NH₂, CN;

R₁ and R₈ may together form a ring of 5-6 atoms;

R is independently H, a straight or branched alkyl of 1-6 carbons,(CH₂)_(n)Ph, or a (CH₂)_(n)heterocycle of 5-6 atoms containing 1-4heteroatoms and wherein the (R)₂ in N(R)₂ optionally forms a heterocyclecontaining the nitrogen, all optionally substituted by F, Cl, Br, OR₉,CN, CO₂R₉, N(R₉)₂, NR₉COR₉, CF₃, or ═O;

R₉ is independently H, a straight or branched alkyl of 1-4 carbons, orphenyl;

R₁₀ is independently H, a straight or branched alkyl of 1-4 carbons, F,Cl, Br, OR₉ or N(R₉)₂;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉ and R₁₀ may be alkene or alkyne offrom 2 to 6 carbon atoms;

Ar₁ and Ar₂ are independently phenyl or Het;

Het is a heterocycle of from 5-6 atoms having from 1-4 heteroatoms or afused heterocycle of from 9-10 atoms having 1-3 heteroatoms

wherein the heteroatoms are independently N, O or S,

A compound, which upon administering to mammals such as a human beingconverts into a compound according to Formula, I is within the scope ofthis invention.

DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention is based in great part on the discovery of theinventors that novel 3-position Nitrogen substituted6,6-disubstituted-5, 6-dihydropyrones and related compounds possessantiviral properties. The HIV protease activities of these compounds arenot dependent on the pH of the environment in which they act. Thebinding affinities to HIV protease measured in vitro, at different pHmediums namely 4.7 and 6.2 were the same. The compounds possessing3-position sulfur substituted 6,6-disubstituted-5, 6-dihydropyronesexhibited higher binding affinities at lower pH (namely 4.7) compared tohigher pH (namely 6.2) of the assay medium ( Tummino, P. J.; VaraPrasad, J. V. N.; Ferguson, D.; Nouhan, C.; Graham, N.; Domagala, J.;Ellsworth, E.; Gajda, C.; Hagen, S. E.; Lunney, E. A.; Para, K. S.;Tait, B. D.; Pavlovlsky, A.; Erickson, J. W.; Gracheck, S.; McQuade, T.J.; Hupe, D. J. BioOrganic and Medicinal Chemistry 1996, 4(9),1401-1410; Tait, B. D., Hagen, S., Domagala, J. M., Ellsworth, E.,Gajda, C., Hamilton, H., Vara Prasad, J. V. N., Ferguson, D., Graham,N., Hupe, D., Nouhan, C., Tummino, P. J., Humblet, C., Lunney, E. A.,Pavlovsky, A., Rubin, J., Baldwin, E. T., Bhat, T. N., Erickson, J. W.,Gulnik, S. V., Liu, B. J. Med. Chem., 1997, 40, 3781). (Table 1).

TABLE 1 IC₅₀s (μM) measured in vitro against HIV protease enzymeCompound pH (4.7) pH (6.2)

0.028 0.28

0.010 0.035

0.004 0.004 IC₅₀ indicates the concentration of the inhibitor at 50%inhibition.

The compounds of the present invention lacks chiral center at the3-position of the 6, 6-disubstituted-5,6-dihydropyrones, unlike3-position carbon containing 6,6-disubstituted-5, 6-dihydropyrones.(Upjohn's patents; Thaisrivongs, S.; Skulnick, H. I.; Turner, S. R.;Strobach, J. W.; Tommasi, R. A.; Johnson, P. D.; Aristoff, P. A.; Judge,T. M.; Gammill, R. B.; Morris, J. K.; Romines, K. R.; Chrusciel, R. A.;Hinshaw, R. R.; Chong, K.-T.; Tarpley, W. G.; Poppe, S. M.; Slade, D.E.; Lynn, J. C.; Horng, M.-M.; Tomich, P. K.; Seest, E. P.; Dolak, L.A.; Howe, W. J.; Howard, G. M.; Schwende, F. J.; Toth, L. N.; Padbury,G. E.; Wilson, K. F.; Rush, B. D.; Ruwart, M. J.; Koeplinger, K. A.;Zhao, Z.; Cole, S.; Zaya, R. M.; Kakuk, T. J.; Janakiraman, M. N.;Watenpaugh, K. D. J. Med. Chem., 1996, 39, 5349). The lack of chiralcenters at 3-position offers an obvious synthetic advantage. Thus thesecompounds are easy to synthesize compared to 3-position carboncontaining 6,6-disubstituted-5, 6-dihydropyrones.

Moreover, the substituents at 6-position of the6,6-disubstituted-3-nitrogen substituted-5, 6-dihydropyrones occupydifferent binding pockets of the HIV protease as revealed by X-raycrystal structure of compound 1 binding to HIV protease when compared tothe similar substitutents present in 3-carbonsubstituted-6,6-disubstituted-5, 6-dihydropyrones (for examplePNU-140690; Thaisrivongs, S.; Skulnick, H. I.; Turner, S. R.; Strobach,J. W.; Tommasi, R. A.; Johnson, P. D.; Aristoff, P. A.; Judge, T. M.;Gammill, R. B.; Morris, J. K.; Romines, K. R.; Chrusciel, R. A.;Hinshaw, R. R.; Chong, K.-T.; Tarpley, W. G.; Poppe, S. M.; Slade, D.E.; Lynn, J. C.; Horng, M.-M.; Tomich, P. K.; Seest, E. P.; Dolak, L.A.; Howe, W. J.; Howard, G. M.; Schwende, F. J.; Toth, L. N.; Padbury,G. E.; Wilson, K. F.; Rush, B. D.; Ruwart, M. J.; Koeplinger, K. A.;Zhao, Z.; Cole, S.; Zaya, R. M.; Kakuk, T. J.; Janakiraman, M. N.;Watenpaugh, K. D. J. Med. Chem., 1996, 39, 5349). It is interesting tonote that PNU-140690 contains n-propyl and phenethyl groups at the6-position of the 5,6-dihydropyran-2-one ring, somewhat similar toExample 1. However, n-propyl and phenethyl groups in PNU-140690 occupyS₂ and S₁ pocket of the enzyme, respectively. This orientation contrastswith Example 1, wherein the small alkyl group (isopropyl) occupies theS₁ pocket of the enzyme and 4-substituted phenethyl group occupies S₂pocket. This result clearly demonstrates that different enantiomers aremost active in these two series of HIV PR inhibitor, despite the commoncore. The differences in these two series is shown in a schematicdiagram below:

These 3-position nitrogen substituted 5,6-dihydropyrones are expected tobe extremely useful in the development of treatments for infectionscaused by viruses, especially by retroviruses that rely on aspartylprotease activities for replication and infectivity. One such retrovirusis HIV. For this reason, the antiviral 5,6-dihydropyrones are alsoexpected to be very useful in the treatment of diseases and syndromesassociates with viral pathogens. One such syndrome is AIDS.

Preferred compounds of Formula I are those wherein:

R₁ is isopropyl, iso-butyl, cyclopentyl, cyclohexyl or t-butyl;

R₂ is H, methyl, or ethyl;

R is H, a straight or branched alkyl of 1-4 carbons, (CH₂)_(n)Ph, or a(CH₂)_(n)heterocycle of 5-6 atoms containing 1-2 heteroatoms and whereinthe (R)₂ in N(R)₂ may form a heterocycle containing the nitrogen, alloptionally substituted by F, Cl, Br, OR₉, N(R₉)₂, N(R₉)COR₉, CF₃, or ═O;

wherein Het is a heterocycle of from 5-6 atoms having 1-4 heteroatomsselected from: furan, pyrrole, thiophene, oxazole, isoxazole, thiazole,pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine,pyridazine, pyrimidine, pyrazine, tetrahydrofuran, tetrahydrothiophene,pyrrolidine, piperazine, piperidine, morpholine, thiomorpholine,oxolane, dioxane, sulfolane; or a fused heterocycle of from 9-10 atomshaving from 1-3 heteroatoms selected from: benzofuran, indole,benzothiophene, benzimidazole, benzthiazole, benzoxazole, quinoline,isoquinoline, cinnoline, quinazoline and quinoxaline.

X is NH.

Other preferred compounds of Formula I are those wherein:

R₁ is isopropyl or t-butyl;

R₂ is H, methyl or ethyl;

R₃ is H, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, (CH₂)_(n)N(R₉)COR,(CH₂)_(n)CON(R)₂, (CH₂)_(n)OC(O)N(R)₂, (CH₂)_(n)N(R₉)CON(R)₂,(CH₂)_(n)N(R₉)CO₂R, (CH₂)_(n)OSO₂N(R)₂, (CH₂)_(n)N(R₉)SO₂OR,(CH₂)_(n)N(R₉)SO₂N(R)₂, (CH₂)_(n)OSOR, (CH₂)_(n)N(R₉)SO₂R,(CH₂)_(n)SO₂R, (CH₂)_(n)N(R₉)C(S)N(R)₂, (CH₂)_(n)COR, O(CH₂)_(m)O(R₉),N(R)(CH₂)_(m)O(R₉), or C(CH₃)₂R_(9;)

R₄, R₅, and R₆ are independently H, a straight or branched alkyl of 1-6carbons, a cycloalkyl of 3-6 carbons, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, F,Cl, Br, CN, CF₃, ═O, (CH₂)_(n)N(R₉)COR, (CH₂)_(n)N(R₉)CON(R)₂,(CH₂)_(n)OC(O)N(R)₂, (CH₂)_(n)N(R₉)CO₂R, (CH₂)_(n)COR, (CH₂)_(n)CON(R)₂,(CH₂)_(n)N(R₉)SO₂R, (CH₂)_(n)N(R₉)SO₂R, (CH₂)_(n)OSO₂N(R)₂, or R₄ and R₅may together form a ring of 5-6 total atoms which may contain 0-2heteroatoms,

R is H, a straight or branched alkyl of 1-4 carbons, (CH₂)_(n)Ph, or a(CH₂)_(n)heterocycle of 5-6 atoms containing 1-2 heteroatoms and whereinthe (R)₂ in N(R)₂ may be a heterocycle containing the nitrogen, alloptionally substituted by F, Cl, Br, OR₉, N(R₉)₂, N(R₉)COR₉, or ═O;

R₈ is an alkyl group of 1-5 carbons or a carbocycle of 3-6 atoms;

Ar₁ is a phenyl; and

Ar2 is phenyl or heterocycle of 5-6 atoms having from 14 heteroatoms.

Still other preferred compounds of Formula I are those wherein:

R₃ is H, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, (CH₂)_(n)NR₉COR, (CH₂)_(n)CON(R)₂,(CH₂)_(n)OCON(R)₂, (CH₂)_(n)NR₉CON(R)₂ (CH₂)_(n)NR₉CO₂R,(CH₂)_(n)OSON(R)₂, (CH₂)_(n)NR₉SO₂OR, (CH₂)_(n)NR₉SO₂N(R)₂,(CH₂)_(n)OSO₂R, (CH₂)_(n)NR₉SO₂R, (CH₂)_(n)SO₂R, (CH₂)_(n)COR,O(CH₂)_(m)OR, NR(CH₂)_(m)OR, C(CH₃)₂OR₉, F, Cl, Br, CF₃, or ═O when Aris Het;

R₄, R₅, and R₆ are independently H, a straight or branched alkyl of 1-6carbons, a cycloalkyl of 3-6 carbons, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, F,Cl, Br, ═O when Ar is Het, (CH₂)_(p)N(R₉)COR, (CH₂)_(n)N(R₉)CON(R)₂,(CH₂)_(n)OC(O)N(R)₂, (CH₂)_(n)N(R₉)CO₂R, (CH₂)_(n)COR,(CH₂)_(n)C(O)N(R)₂, (CH₂)_(n)N(R₉)SO₂R, (CH₂)_(n)N(R₉)SO₂OR,(CH₂)_(n)OSON(R)₂;

R₁ and R₂ or R₄ and R₅ may together form a ring of 5-6 total atoms,which may contain 0-2 heteroatoms;

R₇ is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl;

R₈ is a straight or branched alkyl of 1-5 carbons;

R is H, a straight or branched alkyl of 1-4 carbons, (CH₂)_(n)Ph, or a(CH₂)_(n)heterocycle of 5-6 atoms containing 1-2 heteroatoms and whereinthe (R)₂ in N(R)₂ may be a heterocycle containing the nitrogen, alloptionally substituted by F, Cl, Br, OR₉, N(R₉)₂, N(R₉)COR₉, or ═O;

Still other preferred compounds of Formula I are those wherein:

R₃ is H, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, (CH₂)_(n)N(R₉)COR,(CH₂)_(n)C(O)N(R)₂, (CH₂)_(n)OCON(R)₂, (CH₂)_(n)N(R₉)CON(R)₂,(CH₂)_(n)N(R₉)CO₂R, (CH₂)_(n)OSO₂N(R)₂, (CH₂)_(n)N(R₉)SO₂OR,(CH₂)_(n)N(R₉)SO₂N(R)₂, (CH₂)_(n)OSOR, (CH₂)_(n)N(R₉)SO₂R,(CH₂)_(n)SO₂R, (CH₂)_(n)COR, O(CH₂)_(m)OR₉, N(R)(CH₂)_(m)OR₉,C(CH₃)₂OR₉, F, Cl, Br, CF₃, or ═O when Ar is Het;

Any two of R₁-R₃ may together form a ring of 5-6 total atoms, which maycontain 0-2 heteroatoms;

R₁ and R₈ may together form a ring to 5-6 atoms;

R₄, R₅, and R₆ are independently H, a straight or branched alkyl of 1-6carbons, a cycloalkyl of 3-6 carbons, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, F,Cl, Br, CF₃, (CH₂)_(n)N(R₉)COR, (CH₂)_(n)NR₉CON(R)₂,(CH₂)_(n)OC(O)N(R)₂, (CH₂)_(n)N(R₉)CO₂R, (CH₂)_(n)C(O)R,(CH₂)_(n)C(O)N(R)₂, (CH₂)_(n)N(R₉)SO₂R, (CH₂)_(n)NR₉SO₂OR,(CH₂)_(n)OSO₂N(R)₂, (CH₂)_(n)Het;

any two of R₄-R₆ may together form a ring of 5-6 total atoms, which maycontain 0-2 heteroatoms;

R₈ is a straight or branched alkyl of 1-5 carbons or a carbocycle of 3-6atoms.

More preferred compounds of Formula I are those wherein:

R₁ is H;

R₂ is H;

R₃ is H, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, (CH₂)_(n)OCON(R)₂,(CH₂)_(n)N(R₉)CON(R)₂, (CH₂)_(n)N(R₉)CO₂R, (CH₂)_(n)OSON(R)₂,(CH₂)_(n)N(R₉)SO₂OR, (CH₂)_(n)N(R₉)SO₂N(R)₂, (CH₂)_(n)N(R₉)SO₂R,(CH₂)_(n)SO₂R, O(CH₂)_(m)OR₉, N(R)(CH₂)_(m)OR₉, or C(CH₃)₂OR₉;

R₄, R₅, and R₆ are independently H, a straight or branched alkyl of 1-6carbons, a cycloalkyl of 3-6 carbons, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, F,Cl, Br, ═O when Ar is Het, (CH₂)_(n)N(R₉)COR, (CH₂)_(n)N(R₉)C(O)N(R)₂,(CH₂)_(n)OC(O)N(R)₂, (CH₂)_(n)NR₉CO₂R, (CH₂)_(n)C(O)R,(CH₂)_(n)C(O)N(R)₂, (CH₂)_(n)N(R₉)SO₂R, (CH₂)_(p)N(R₉)SO₂OR,(CH₂)_(p)OSO₂N(R)₂;

R₄ and R₅ may together form a ring of 5-6 total atoms, which may contain0-2 heteroatoms;

R₈ is a straight or branched alkyl of 1-5 atoms or a carbocycle of 3-6atoms;

R is H, a straight or branched alkyl of 1-4 carbons, (CH₂)_(n)Ph, or a(CH₂)_(n)heterocycle of 5-6 atoms having from 1-2 heteroatoms andwherein the (R)₂ in N(R)₂ may be a heterocycle containing the nitrogen,all optionally substituted by F, Cl, Br, OR₉, N(R₉)₂, N(R₉)C(O)R₉, or═O;

R₁ and R₈ may together form a ring of 5-6 atoms.

Ar₁ is phenyl; and

Ar2 is phenyl, furan, pyrrole, thiophene, oxazole, isoxazole, thiazole,pyrazole, tetrazole, or pyridine.

Other more preferred compounds of Formula I are those wherein:

R₂ is H;

R₃ is H, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, (CH₂)_(n)N(R)COR,(CH₂)_(n)CON(R)₂, (CH₂)_(n)OC(O)N(R)₂, (CH₂)_(n)N(R₉)C(O)N(R)₂,(CH₂)_(n)N(R₉)CO₂R, (CH₂)_(n)OSON(R)₂, (CH₂)_(n)N(R₉)SO₂R,(CH₂)_(n)N(R₉)SO₂N(R)₂, (CH₂)_(n)OSO₂R, (CH₂)_(n)N(R₉)SO₂R,(CH₂)_(n)SO₂R, O(CH₂)_(m)OR, NR(CH₂)_(m)OR₉, C(CH₃)₂OR₉, or ═O when Aris Het,

R₄, R₅, and R₆ are independently H, a straight or branched alkyl of 1-6carbons, a cycloalkyl of 1-6 carbons, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, F,Cl, Br, ═O when Ar is Het, (CH₂)_(p)N(R₉)COR, (CH₂)_(p)N(R₉)C(O)N(R)₂,(CH₂)_(n)OC(O)N(R)₂, (CH₂)_(n)N(R₉)CO₂R, (CH₂)_(n)COR, (CH₂)_(n)CON(R)₂,(CH₂)_(n)N(R₉)SO₂R, (CH₂)_(n)N(R₉)SO₂OR, (CH₂)_(n)OSON(R)₂;

R₄ and R₅ may together form a ring of 5-6 total atoms, which may contain0-2 heteroatoms;

R₈ is ethyl, propyl, butyl;

R is H, a straight or branched alkyl of 1-4 carbons, (CH₂)_(n)Ph, or a(CH₂)_(n)heterocycle of 5-6 atoms containing 1-2 heteroatoms and whereinthe (R)₂ in N(R)₂ may be a heterocycle having nitrogen, all optionallysubstituted by F, Cl, Br, OR₉, N(R₉)₂, NR₉CO(R₉), or ═O;

Ar₁ is phenyl, thiophene, thiazole, pyridine, benzothiophene,benzthiazole, benzoxazole, quinoline or isoquinoline.

Still other more preferred compounds of formula I are those wherein:

R₂ is H;

R₃ is CH₂OH, NH₂OCH₂CH₂OH, NHCOR, OSO₂N(R)₂, N(R₉)SO₂OR, N(R₉)SO₂R, orOSO₂R;

R₄, R₅ and R₆ are independently H, a straight or branched alkyl of 1-6carbons, a cycloalkyl of 1-6 carbons, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, F,Cl, Br, ═O when Ar is Het, (CH₂)_(n)NR₉COR, (CH₂)_(n)NR₉CON(R)₂,(CH₂)_(n)OCON(R)₂, (CH₂)_(n)NR₉CO₂R, (CH₂)_(n)COR, (CH₂)_(n)CON(R)₂,(CH₂)_(n)NR₉SO₂R, (CH₂)_(n)NR₉SO₂OR, (CH₂)_(n)OSO₂N(R)₂;

R₄ and R₅ may together form a ring of 5-6 total atoms, which may contain0-2 heteroatoms;

R is H, a straight or branched alkyl of 1-4 carbons, (CH₂)_(n)Ph, or a(CH₂)_(n)heterocycle of 5-6 atoms having from 1-2 heteroatoms andwherein the (R)₂ in N(R)₂ may be a heterocycle having nitrogen, alloptionally substituted by F, Cl, Br, OR₉, N(R₉)₂, NR₉COR₉, or ═O;

R₁₀ is H, a straight or branched alkyl of from 1-4 carbons, F, Cl, Br,OR₉, or N(R₉)₂;

Ar₁ is phenyl; and

Ar2 is a heterocycle of 5-6 atoms having from 1-4 heteroatoms;

Still other more preferred compounds of Formula I are those wherein;

R₁ is H.;

R₂ is H;

R₃ is H, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, (CH₂)_(n)N(R₉)COR,(CH₂)_(n)C(O)N(R)₂, (CH₂)_(n)OC(O)N(R)₂, (CH₂)_(n)N(R₉)C(O)N(R),(CH₂)_(n)N(R₉)CO₂R, (CH₂)_(n)OSON(R)₂, (CH₂)_(n)N(R₉)SO₂OR,(CH₂)_(n)N(R₉)SO₂N(R)₂, (CH₂)_(n)OSO₂R, (CH₂)_(n)N(R₉)SO₂R,(CH₂)_(n)SO₂R, (CH₂)_(n)N(R₉)C(S)N(R)₂, (CH₂)_(n)COR, O(CH₂)_(m)OR,NR(CH₂)_(m)OR₉, C(CH₃)₂R₉, F, Cl, Br, or ═O when Ar is Het;

R₄, R₅ and R₆ are independently H, methyl, ethyl, OH, CH₂H, CH₂CH₂H, F,Cl, NH₂;

any two R₄-R₆ may form a ring of 5-6 atoms having from 1-2 heteroatoms;

R₈ is ethyl, propyl, butyl;

R is H, a straight or branched alkyl of 1-4 carbons, (CH₂)_(n)Ph, or a(CH₂)_(n)heterocycle of 5-6 atoms having from 1-2 heteroatoms or aheterocycle having a nitrogen, all optionally substituted by F, Cl, Br,OR₉, N(R₉)₂, NR₉OR₉ or ═O;

Ar₁ is phenyl, furan, thiophene, thiazole, pyridine, imidazole,benzofuran, benzothiophene, benzimidazole, benzthiazole, quinoline, orisoquinoline; and

Ar₂ is phenyl.

Still other more preferred compounds of formula I are those wherein:

R₁ is H or methyl;

R₂ is H or methyl;

R₃ is H, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, or ═O;

R₄, R₅, and R₆ are independently H, methyl, OH, CH₂H, CH₂CH₂H, NH₂or F;

R₇ is H, isopropyl, butyl, sec-butyl, cyclobutyl, cyclopentyl, orcyclohexyl;

R₈ is ethyl, propyl, butyl;

R is H, methyl, ethyl, phenyl, or CH₂Ph and wherein the (R)₂ of N(R)₂may be a heterocycle having a nitrogen;

R₁₀ is H, F, or CH₃;

Ar₁ is phenyl, furan, thiophene, thiazole, pyridine, imidazole, indole,benzofuran, benzothiophene, benzimidazole, benzthiazole, quinoline, orisoquinoline; and

Ar2 is phenyl, furan, thiophene, thiazole, pyridine, imidazole, indole,benzofuran, benzothiophene, benzimidazole, benzthiazole, quinoline, orisoquinoline.

Other preferred compounds of Formula I are those wherein:

R₁ is H or methyl;

R₂ is H or methyl;

R₃ is H, NH₂OH, CH₂R, CH₂N(R)₂, CH₂CON(R)₂, CH₂OSO₂N(R)₂, CH₂NHSO₂R,CH₂NHSO₂R, CH₂OSO₂R, Cl, Br, or OCH₂CH₂H;

R₄, R₅, and R₆ are independently H, methyl, ethyl, isopropyl, OH,NH₂CH₂R, CH₂N(R)₂, ═O, F, Cl, Br, or CH₂NRCOR;

R₇ is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl;

R₈ is ethyl, propyl, butyl;

R is H, methyl, ethyl, Ph, CH₂Ph, and wherein the (R)₂ in N(R)₂ may be aheterocycle having a nitrogen;

R₁ and R₈ may together form a ring of 5-6 total atoms;

R₁₀ is H, F, or CH₃;

Ar₁ is phenyl, thiophene, thiazole, furan, pyridine, benzothiophene,benzofuran, benzthiazole, benzoxazole, indole, quinoline, orisoquinoline; and

Ar2 is phenyl, furan, thiophene, oxazole, isoxazole, imidazole,thiazole, pyrazole, pyridine, benzofuran, benzothiophene, benzimidazole,benzthiazole, indole, quinoline, or isoquinoline; and

f is an integer of 2.

Other preferred compounds of Formula I are those wherein:

R₁ is H;

R₂ is H;

R₃ is H, NH₂OH, CH₂R, CH₂N(R)₂, CH₂CON(R)₂, OSO₂N(R)₂, NHSO₂OR, NHSO₂R,OSO₂R, or OCH₂CH₂H;

R₄, R₅, and R₆ are independently H, methyl, ethyl, isopropyl, OH,NH₂CH₂R, CH₂N(R)₂, ═O when Ar is Het, F, Cl, Br, or CH₂NRCOR;

R₇ is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, orcyclopentyl;

R₈ is ethyl, propyl, butyl;

R is H, methyl, ethyl, Ph, CH₂Ph, and wherein the (R)₂ in N(R)₂ may be aheterocycle containing the nitrogen;

R₁₀ is H, F, or CH₃;

R₁ and R₈ may together form a ring of 5-6 total atoms;

Ar₁ is phenyl, furan, thiophene, oxazole, isoxazole, imidazole,thiazole, pyrazole, pyridine, benzofuran, benzothiophene, benzimidazole,benzthiazole, indole, quinoline, or isoquinoline; and

Ar2 is phenyl, furan, thiophene, oxazole, isoxazole, imidazole,thiazole, pyrazole, pyridine, benzofuran, benzothiophene, benzimidazole,benzthiazole, indole, quinoline, or isoquinoline.

Still other preferred compounds of Formula I are those wherein:

R₁ is H;

R₂ is H;

R₃ is NH₂CH₂H, OCH₂CH₂H, CH₂CH₂H, or NHSO₂Ar₁;

R₄, R₅, and R₆ are independently H, NH₂CH₂H, ═O when Ar is Het, methyl,ethyl, or isopropyl;

R₇ is n-propyl, isopropyl or tert-butyl;

R₈ is ethyl, propyl or n-butyl;

R₁₀ is H, F, or CH₃;

Ar₁ is phenyl; and

Ar2 is phenyl, furan, thiophene, imidazole, thiazole, indole, pyrazole,or pyridine;

f is an integer of value 2.

Especially preferred compounds of the invention are:

5-Trifluoromethyl-pyridine-2-sulfonic acid{3-[(4-hydroxy-6-isopropyl-2-oxo-6-phenethyl-5,6-dihydro-2H-pyran-3-yl)-propyl-amino]-phenyl}-amide;

5-Trifluoromethyl-pyridine-2-sulfonic acid[3-({4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-phenyl]-amide;

5-Trifluoromethyl-pyridine-2-sulfonic acid{3-[ethyl-(4-hydroxy-6-isopropyl-2-oxo-6-phenethyl-5,6-dihydro-2H-pyran-3-yl)-amino]-phenyl}-amide;

5-Trifluoromethyl-pyridine-2-sulfonic acid[3-({4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-yl }-propyl-amino)-phenyl]-amide;

5-Trifluoromethyl-pyridine-2-sulfonic acid[3-(ethyl-{4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-2-oxo-6-propyl-5,6-dihydro-2H-pyran-3-yl}-amino)-phenyl]-amide;

5-Trifluoromethyl-pyridine-2-sulfonic acid[3-(ethyl-{4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-yl}-amino)-phenyl]-amide;

4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;

6-Cyclopentyl-4-hydroxy-6-[2-(3-hydroxy-phenyl)-ethyl]-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;

4-Hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;

Thiophene-2-sulfonic acid[3-({4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-phenyl]-amide;

5-Trifluoromethyl-pyridine-2-sulfonic acid[3-({4-hydroxy-6-(2-phenyethyl)-6-(n-propyl)-2-oxo-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-phenyl]-amide;

5-Trifluoromethyl-pyridine-2-sulfonic acid[3-({6-cyclopentyl-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-2-oxo-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-phenyl]-amide;

3-(Butyl-phenyl-amino)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

Pyridine-2-sulfonic acid[3-({4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-phenyl]-amide;

3-(Butyl-phenyl-amino)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

3-(Butyl-phenyl-amino)-6-cyclopentyl-4-hydroxy-6-[2-(3-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one;

5-Trifluoromethyl-pyridine-2-sulfonic acid[3-({6-[2-(4-amino-phenyl)-ethyl]-4-hydroxy-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-phenyl]-amide;

3-[(3,4-Dichloro-phenyl)-propyl-amino]-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

4-Hydroxy-3-[(3-hydroxymethyl-phenyl)-propyl-amino]-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

3-({4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-yl}-phenyl-amino)-propionitrile;

3-Diphenylamino-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;and

Pyridine-2-sulfonic acid{3-[ethyl-(4-hydroxy-6-isopropyl-2-oxo-6-phenethyl-5,6-dihydro-2H-pyran-3-yl)-amino]-phenyl}-amide.

The term “alkyl” means a straight or branched hydrocarbon radical havingfrom 1 to 12 carbon atoms unless otherwise specified and includes, forexample, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl,n-decyl, undecyl, and dodecyl. The alkylene or alkyne groups may containone or more sites of unsaturation such as double or triple carbon-carbonbonds. The alkyl group is unsubstituted or substituted by from 1 to 3substituents selected from F, Cl, Br, OH, NH₂, CN, NO₂, OCH₃, OCH₂CH₂H,NHCH₃, or N(CH₃)₂.

The term “cycloalkyl” means a hydrocarbon ring, which contains from 3 to12 carbon atoms unless otherwise specified, for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl. Where possible, thecycloalkyl group may contain double bonds. The cycloalkyl ring may beunsubstituted or substituted by from 1 to 3 substituents selected fromalkyl, alkoxy, thioalkoxy all as defined herein, hydroxy, thiol, nitro,halogen, amino, formyl, carboxyl, nitrile, —NH—CO—R, —CO—NHR—, —CO₂R,—COR, aryl, or heteroaryl wherein alkyl (R), aryl, and heteroaryl aredefined as herein.

The term “carbocycle” means cycloalkyl as defined above.

The term “heteroatoms” means a nitrogen, sulfur, or oxygen.

The term “heterocycle” means a heterocyclic radical which are 5-6 atomshaving 1-4 heteroatoms and selected from 1-4 heteroatoms or a fusedheterocycle of from 9-10 atoms having 1-3 heteroatoms selected from:furan, pyrrole, thiophene, oxazole, isoxazole, thiazole, pyrazole,1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine,pyrimidine, pyrazine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine,piperazine, piperidine, morpholine, thiomorpholine, oxolane, dioxane,sulfolane, unsubstituted or substituted by 1 to 2 substituents selectedfrom alkyl as defined above. For heterocycles containing sulfur, theoxidized sulfur heterocycles containing SO or SO₂ groups are alsoincluded.

The term “fused heterocycle” refers to a heterocycle that is adjoined astwo consecutive positions with a phenyl ring or another heterocycle.such rings may include 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-,4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl,2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or7-benzothiazolyl.

For purposes of the syntheses of the compounds of the present invention,reactive functional groups present in starting materials, reactionintermediates, or reaction products may be protected during chemicalreactions using protecting groups which render the reactive functionalgroups substantially inert to the reaction conditions (see for example,Protective Groups in Organic Synthesis, 2nd ed., T. W. Green and P. G.Wuts, John Wiley & Sons, New York, NY 1991). Thus, for example,protecting groups such as the following may be utilized to protectsuitable amino, hydroxyl, and other groups of related reactivity:carboxylic acyl groups, such as formyl, acetyl, trifluoroacetyl;alkoxycarbonyl groups, such as ethoxycarbonyl, t-butoxycarbonyl (BOC),β,β,β-trichloroethoxycarbonyl (TCEC), β-iodoethoxycarbonyl;aryloxycarbonyl groups, such as benzyloxycarbonyl,p-methoxybenzyloxycarbonyl, phenoxycarbonyl; trialkyl silyl groups, suchas trimethylsilyl and t-butyldimethylsilyl (TBDMS); and groups such astrityl, tetrahydropyranyl, vinyloxycarbonyl, o-nitrophenylsulfenyl,diphenylphosphinyl, p-toluenesulfonyl, and benzyl may all be utilized.The protecting group may be removed, after completion of the syntheticreaction of interest, by procedures known to those skilled in the art.For example, a BOC group may be removed by acidolysis, a trityl group byhydrogenolysis, TBDMS by treatment with fluoride ions, and TCEC bytreatment with zinc.

Some of the compounds of Formula I are capable of further formingpharmaceutically acceptable acid-addition and/or base salts. All ofthese forms are within the scope of the present invention.

Pharmaceutically acceptable acid addition salts of the compounds ofFormula I include salts derived from nontoxic inorganic acids such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic,hydrofluoric, phosphorous, and the like, as well as the salts derivedfrom nontoxic organic acids, such as aliphatic mono- and dicarboxylicacids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids,alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonicacids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate,sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate,dihyrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate,oxalate, malonate, succinates suberate, sebacate, fumarate, maleate,mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate,lactate, maleate, tartrate, methanesulfonate, and the like. Alsocontemplated are salts of amino acids such as arginate and the like andgluconate, galacturonate (see, for example, Berge S.M., et al.,“Pharmaceutical Salts,” Journal of Pharmaceutical Science, 1977;66:1-19.

The acid addition salt of said basic compounds are prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner.

Pharmaceutically acceptable base addition salts are formed with metalsor amines, such as alkali and alkaline earth metals or organic amines.Examples of metals used as cations are sodium, potassium, magnesium,calcium, and the like. Examples of suitable amines areN,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine(see, for example, Berge, supra., 1977).

The base addition salts of said acidic compounds are prepared bycontacting the free acid form with a sufficient amount of the desiredbase to produce the salt in the conventional manner.

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

Certain of the compounds of the present invention possess one or morechiral centers and each center may exist in the R(D) or S(L)configuration. The present invention includes all enantiomeric andepimeric forms as well as the appropriate mixtures thereof Configurationdrawn is most preferred.

The compounds of the present invention can be prepared and administeredin a wide variety of oral and parenteral dosage forms. Thus, thecompounds of the present invention can be administered by injection,that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Also, thecompounds of the present invention can be administered by inhalation,for example, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally. It will be obvious to thoseskilled in the art that the following dosage forms may comprise as theactive component, either a compound of Formula I or a correspondingpharmaceutically acceptable salt of a compound of Formula I.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances, which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted, and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or, synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations, which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is divided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 100 mg preferably 0.5 mg to 100 mgaccording to the particular application and the potency of the activecomponent. The composition can, if desired, also contain othercompatible therapeutic agents.

In therapeutic use as antagonists of a retroviral protease, as agentsfor the treatment of infections caused by a retrovirus including HIV, oras agents for the treatment of diseases due to AIDS, the compoundsutilized in the pharmaceutical method of this invention are administeredat the initial dosage of about 0.01 mg to about 100 mg/kg daily. A dailydose range of about 0.01-mg to about 10 mg/kg is preferred. The dosages,however, may be varied depending upon the requirements of the patient,the severity of the condition being treated, the compound beingemployed. Determination of the proper dosage for a particular situationis within the skill of the art. Generally, treatment is initiated withsmaller dosages, which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under the circumstances is reached. For convenience, thetotal daily dosage may be divided and administered in portions duringthe day, if desired.

The compounds of the present invention can be prepared according to thevarious synthetic schemes that follow. Protecting groups may be usedwhen appropriate throughout many of the schemes. Although specificallynoted in certain schemes, the appropriate use and choice of protectinggroups is well known by one skilled in the art, and is not limited tothe specific examples below. It is also understood that such groups notonly serve to protect chemically reactive sites, but also to enhancesolubility or otherwise change physical properties. A good generalreference for protecting group preparation and deprotection is“Protective Groups in Organic Synthesis” by Theodora Green, supra. Anumber of general reactions such as oxidations and reductions are notshown in detail but can be done by methods understood by one skilled inthe art. General transformations are well reviewed in “ComprehensiveOrganic Transformation” by Richard Larock, and the series “Compendium ofOrganic Synthetic Methods” (1989) published by Wiley-Interscience. Ingeneral, the starting materials were obtained from commercial sourcesunless otherwise indicated.

Synthesis of Compounds

There are two steps of the synthesis of desired products: 1) thepreparation of diazocompounds from 6,6-disubstituted-5,6-dihydropyrones;3) coupling of amines to diazo derivatives of6,6-disubstituted-5,6-dihydropyrones to complete the preparation of thecompounds of the invention (Scheme 1).

Preparation of 6,6-disubstituted-5,6-dihydropyrones

Racemic as well as enantiomerically pure 5,6-dihydropyrones weresynthesized as described in U.S. patents referred to above.

Preparation of 3-diazo-6,6disubstituted-5,6-dihydropyrones (step 1)

To the 6,6-disubstituted-5,6-dihydropyrone (1 eq.) taken in a solventlike DMF was added sodium hydrogen phosphate (monobasic) (1-2 eq.),followed by (p-acetylamino)-phenylsulfonylazide (1-1.5 eq.). Afterstirring the reaction at room temperature for 3 to 16 hours. Thereaction was quenched by adding a saturated aqueous solution of sodiumhydrogen phosphate (dibasic) and diluted with ethyl acetate. Organiclayer was separated and aqueous layer was extracted with ethyl acetate(3-4 times). Combined organic layer was dried over MgSO₄ andconcentrated. The crude product was purified by flash silica gelchromatography to afford pure3-diazo-6,6-disubstituted-5,6-dihydropyrones.

Coupling of amines to 3-diazo-6,6-disubstituted-5,6-dihydropyrones (step2)

The 3-diazo-6,6-disubstituted-5,6-dihydropyrone (1 eq.) was dissolved inan aromatic hydrocarbon solvent like benzene or toluene. To thissolution the amine (3-10 eq was added followed by rhodium (III) acetatedimer (0.01 to 0.2 eq.). The reaction was kept at 80° C. for 2 to 6hours. The reaction mixture was cooled and diluted with ethyl acetate.The organic layer was washed with dilute hydrochloric acid, brine anddried over MgSO₄. Organic layer was concentrated and the crude productwas purified by flash silica gel chromatography to afford the finalproduct.

The amines used in the step 2 were either commercially available orprepared as described below:

The amines, which can be used in Scheme 1, step 2; are prepared byreductive amination of the corresponding appropriately substitutedanilines with aldehydes by a number of methods. One of the methodsinvolve the use of reducing agents like sodium cyanoborohydride; whereasthe other method involved the use of a heterogeneous catalysts likeRaney nickel or Palladium on carbon under hydrogen atmosphere. Organiclayer was concentrated and the crude product was purified by flashsilica gel chromatography to afford the final product.

Preparation of Sulfonamides

Sulfonamides were prepared from the corresponding amines as follows:

6,6-disubstituted-5,6-dihydropyrone (1 eq.) was taken in a halogenatedsolvent like dichlorometane. To this solution pyridine followed bysulfonyl chloride was added. The reaction was kept under stirring atroom temperature for 6 to 18 hours. The reaction was quenched withdilute hydrochloric acid (1N) and diluted with ethyl acetate. Theorganic layer was separated; concentrated and the crude product waspurified by flash silica gel chromatography to afford the final product.

TABLE A Final Dihydropyrones

Chirality Melting Mass at Point Spe Example Ar₂ C-6 Ar₁ R₇ X (° C.)(APCI) 1

S

Iso-propyl N-(n- propyl) 618 (M + H) 2

S

Iso-propyl N-(n- propyl) 107- 110 634 (M + H) 3

RS

Iso-propyl N- (Ethyl) 604 (M + H) 4

RS

Iso-propyl N-(n- propyl) 634 (M + H) 5

RS

n-propyl N- (Ethyl) 620 (M + H) 6

RS

Iso-propyl N- (Ethyl) 620 (M + H) 7

S

Iso-propyl N-(n- propyl) 171- 173 410 (M + H) 8

S

Cyclo- pentyl N-(n- propyl) 74-76 436 (M + H) 9

RS

Iso-propyl N-(n- propyl) 58-60 425 (M + H) 10

S

Iso-propyl N-(n- propyl) 85-87 571 (M + H) 11

RS

n-propyl N- (Ethyl) 608 (M + H) 12

RS

Cyclo- pentyl N-(n- propyl) 104- 106 660 (M + H) 13

S

Iso-propyl N-(n- propyl) 196- 198 424 (M + H) 14

RS

Iso-propyl N-(n- propyl) >122 575 (M + H) 15

RS

Iso-propyl N-(n- propyl) 69-71 424 (M + H) 16

S

Cyclo- pentyl N-(n- propyl) 64-66 450 (M + H) 17

RS

Iso-propyl N-(n- propyl) 170- 172 633 (M + H) 18

S

Iso-propyl N-(n- propyl) 188- 191 479 (M + H) 19

RS

Iso-propyl N-(n- propyl) 61-63 440 (M + H) 20

RS

Iso-propyl N- (Phenyl) 138- 140 443 (M + H) 21

RS

Iso-propyl N-(2- cyano ethyl) 119- 121 421 (M + H) 22

RS

Iso-propyl N- (Phenyl) 83-85 444 (M + H) 23

RS

Iso-propyl N- (Ethyl) 536 (M + H) 24

S

Iso-propyl N-(n- propyl) 147- 149 395 (M + H) 25

S

Iso-propyl N-(n- propyl) 96-98 468 (M + H) 26

RS

Iso-propyl N-(n- propyl) 86-88 478, 480 (M + H) 27

RS

Iso-propyl N-(n- propyl) 91-96 417 (M + H) 28

RS

Iso-propyl N-(n- propyl) 160- 162 394 (M + H) 29

RS

Iso-propyl N-(n- propyl) 186- 188 411 (M + H) 30

RS

Iso-propyl N-(n- propyl) 53-55 400 (M + H) 31

RS

Cyclo- pentyl N-(n- propyl) 95 436 (M + H) 32

S

Iso-propyl N-(n- propyl) 71-73 440 (M + H) 33

RS

Iso-propyl N- (Ethyl) 63-65 396 (M + H) 34

S

Cyclo- pentyl N- (Phenyl) 90-92 470 (M + H) 35

RS

Iso-propyl N- (Cyclo- hexyl) 104- 106 450 (M + H) 36

RS

Iso-propyl N- (Cyclo- pentyl) 83-85 436 (M + H) 37

S

Iso-propyl N-(n propyl) 555 (M + H) 38

RS

Iso-propyl N- (Phenyl) 95-96 474 (M + H) 39

RS

Methyl N-(n- propyl) 179- 181 382 (M + H) 40

RS

Iso-propyl N- (Phenyl) 95-97 460 (M + H) 41

RS

n-butyl N-(n- propyl) 58-60 424 (M + H) 42

RS

Cyclo- propyl N-(n- propyl) 74-75 408 (M + H) 43

RS

Iso-propyl N-(Iso- propyl) 75-77 410 (M + H) 44

RS

n-propyl N- (Ethyl) 539 (M + H) 45

S

Iso-propyl N- (Ethyl) 166- 169 411 (M + H) 46

RS

methyl N-(n- propyl) 125- 128 591 (M + H) 47

RS

Iso-propyl N-(2- hydroxy ethyl) 85-86 412 (M + H) 48

RS

Isopropyl N-(n- propyl) 85-89 418 (M + H) 49

RS

Iso-propyl N-(n- propyl) 93-95 438 (M + H) 50

RS

methyl N-(n- propyl) 144- 146 397 (M + H) 51

RS

n-propyl N- (Ethyl) 555 (M + H) 52

RS

Iso-propyl N-(Iso- pentyl) 70-72 438 (M + H) 53

RS

Iso-propyl N- (Cyclo- propyl) 102- 104 408 (M + H) 54

RS

Iso-propyl N-(Tert- butyl) 425 (M + H) 55

S

Iso-propyl N-(Iso- propyl) 428 (M + H) 56

RS

Iso-propyl N- (Ethyl) 395 (M + H) 57

RS

Iso-propyl N-(n- propyl) 93-96 476 (M + H) 58

S

Iso-propyl N- (Ethyl) 410 (M + H) 59

RS

Iso-propyl N- (Ethyl) 97-99 446 (M + H) 60

RS

Iso-propyl N- (Ethyl) 86-88 446 (M + H) 61

RS

Iso-propyl N- (Phenyl) 75-77 458 (M + H) 62

RS

Methyl N-(n- propyl) 58-60 506 (M + H) 63

RS

methyl — 188- 190 400 (M + H) 64

RS

Phenyl NH 69-73 429 (M + H) 65

RS

Phenyl NH 99- 101 462 (M + H) The Table above shows the compounds of theinvention as racemic; however, the R and S forms are within the scope ofthe invention. The S form is the preferred.

The compound names corresponding to Examples 1-65 in Table above are:

(1) 5-Trifluoromethyl-pyridine-2-sulfonic acid{3-[(4-hydroxy-6-isopropyl-2-oxo-6-phenethyl-5,6-dihydro-2H-pyran-3-yl)-propyl-amino]-phenyl}-amide;

(2) 5-Trifluoromethyl-pyridine-2-sulfonic acid [3-({4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-phenyl]-amide;

(3) 5-Trifluoromethyl-pyridine-2-sulfonic acid{3-[ethyl-(4-hydroxy-6-isopropyl-2-oxo-6-phenethyl-5,6-dihydro-2H-pyran-3-yl)-amino]-phenyl}-amide;

(4) 5-Trifluoromethyl-pyridine-2-sulfonic acid[3-({4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-phenyl]-amide;

(5) 5-Trifluoromethyl-pyridine-2-sulfonic acid[3-(ethyl-{4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-2-oxo-6-propyl-5,6-dihydro-2H-pyran-3-yl}-amino)-phenyl]-amide;

(6) 5-Trifluoromethyl-pyridine-2-sulfonic acid[3-(ethyl-{4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-yl}-amino)-phenyl]-amide;

(7)4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;

(8)6-Cyclopentyl-4-hydroxy-6-[2-(3-hydroxy-phenyl)-ethyl]-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;

(9)4-Hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;

(10) Thiophene-2-sulfonic acid[3-({4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-phenyl]-amide;

(11) 5-Trifluoromethyl-pyridine-2-sulfonic acid[3-({4-hydroxy-6-[2-(phenethyl)-6-(n-propyl)-2-oxo-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-phenyl]-amide;

(12) 5-Trifluoromethyl-pyridine-2-sulfonic acid[3-({6-cyclopentyl-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-2-oxo-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-phenyl]-amide;

(13)3-(Butyl-phenyl-amino)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

(14) Pyridine-2-sulfonic acid[3-({4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-phenyl]-amide;

(15)3-(Butyl-phenyl-amino)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

(16)3-(Butyl-phenyl-amino)-6-cyclopentyl-4-hydroxy-6-[2-(3-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one;

(17) 5-Trifluoromethyl-pyridine-2-sulfonic acid[3-({6-[2-(4-amino-phenyl)-ethyl]-4-hydroxy-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-phenyl]-amide;

(18)3-[(3,4-Dichloro-phenyl)-propyl-amino]-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

(19)4-Hydroxy-3-[(3-hydroxymethyl-phenyl)-propyl-amino]-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

(20)[2-(4-Amino-phenyl)-ehtyl]-dihenylamino-hydroxy-isopropyl-5,6-dihydro-pyran-2-on;

(21)3-({4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-yl}-phenyl-amino)-propionitrile;

(22)3-Diphenylamino-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

(23) Pyridine-2-sulfonic acid{3-[ethyl-(4-hydroxy-6-isopropyl-2-oxo-6-phenethyl-5,6-dihydro-2H-pyran-3-yl)-amino]-phenyl}-amide;

(24)4-Hydroxy-6-isopropyl-6-phenethyl-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;

(25)3-({4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-benzoicacid methyl ester;

(26)3-[(3,5-Dichloro-phenyl)-propyl-amino]-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

(27)-6-[2-(4-Amino-phenyl)-ethyl]-4-hydroxy-6-isopropyl-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;

(28)4-Hydroxy-6-isopropyl-6-phenethyl-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;

(29)4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;

(30)4-Hydroxy-6-isopropyl-3-(phenyl-propyl-amino)-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;

(31)6-Cyclopentyl-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one,

(32)4-Hydroxy-3-[(3-hydroxymethyl-phenyl)-propyl-amino]-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

(33)3-(Ethyl-phenyl-amino)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

(34)6-Cyclopentyl-3-diphenylamino-4-hydroxy-6-[2-(3-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one;

(35)3-(Cyclohexyl-phenyl-amino)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

(36)3-(Cyclopentyl-phenyl-amino)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

(37) Thiophene-2-sulfonic acid{3-[(4-hydroxy-6-isopropyl-2-oxo-6-phenethyl-5,6-dihydro-2H-pyran-3-yl)-propyl-amino]-phenyl}-amide;

(38)4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-3-[(4-methoxy-phenyl)-phenyl-amino]-5,6-dihydro-pyran-2-one;

(39)4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-methyl-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;

(40)4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-3-[(3-hydroxy-phenyl)-phenyl-amino]-6-isopropyl-5,6-dihydro-pyran-2-one;

(41)6-Butyl-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;

(42)6-Cyclopropyl-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;

(43)4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-3-(isopropyl-phenyl-amino)-5,6-dihydro-pyran-2-one;

(44) 1-Methyl-1H-imidazole-4-sulfonic acid{3-[ethyl-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-amino]-phenyl}-amide;

(45)3-(Ethyl-p-tolyl-amino)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

(46)4-Cyano-N-[3-({4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-methyl-2-oxo-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-phenyl]-benzenesulfonamide;

(47)4-Hydroxy-3-[(2-hydroxy-ethyl)-phenyl-amino]-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

(48)4-Hydroxy-6-isopropyl-3-(phenyl-propyl-amino)-6-[2-(1H-pyrazol-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;

(49)6-(2-Benzo[1,3]dioxol-5-yl-ethyl)-4-hydroxy-6-isopropyl-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;

(50)4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-methyl-3-(propyl-m-tolyl-amino)-5,6-dihydro-pyran-2-one;

(51) 1-Methyl-1H-imidazole-4-sulfonic acid[3-(ethyl-{4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-2-oxo-6-propyl-5,6-dihydro-2H-pyran-3-yl}-amino)-phenyl]-amide;

(52)4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-3-[(3-methyl-butyl)-phenyl-amino]-5,6-dihydro-pyran-2-one;

(53)3-(Cyclopropyl-phenyl-amino)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

(54)3-(tert-Butyl-phenyl-amino)4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

(55)(S)-3-[(4-Fluoro-phenyl)-isopropyl-amino]-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

(56)3-[(3-Amino-phenyl)-ethyl-amino]-4-hydroxy-6-isopropyl-6-phenethyl-5,6-dihydro-pyran-2-one;

(57)4-Hydroxy-3-[(5-hydroxy-naphthalen-1-yl)-propyl-amino]-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

(58)3-(Ethyl-o-tolyl-amino)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

(59)3-(Ethyl-naphthalen-2-yl-amino)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

(60)3-(Ethyl-naphthalen-1-yl-amino)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

(61)3-(Benzyl-phenyl-amino)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

(62) Dimethyl-sulfamic acid3-({4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-methyl-2-oxo-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-phenyl ester;

(63)3-(3,4-Dihydro-2H-quinoxalin-1-yl)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-methyl-5,6-dihydro-pyran-2-one;

(64)4-Hydroxy-3-(2-isopropylphenylamino)-6-phenethyl-6-phenyl-5,6-dihydro-pyran-2-one;

(65)3-(2-tert-Butyl-5-methyl)-phenylamino)-4-hydroxy-6-phenethyl-6-phenyl-5,6-dihydro-pyran-2-one;

The following sections provide the experimental methodology for the invitro and in vivo assays employed to demonstrate the efficacy andadvantages of the compounds of the current invention.

The compounds of the present invention were evaluated for their in vitroinhibition of HIV protease and for their antiviral efficacy in HIVinfected lymphocytes and the results shown in Table 2.

HIV Protease Assay Materials

Recombinant HIV-1 protease (>96% purity) and HIV protease substrate III(the undecapeptide H-His-Lys-Ala-Arg-Val-Leu-Nph-Glu-Ala-Nle-Ser-NH₂,97% purity) were purchased from Bachem Bioscience, Inc. (King ofPrussia, Pa.).

Method

The methods employed follow the procedures of Tummino, et al., Archivesof Biochemistry and Biophysics, 1995;316:523). For determination of Kivalues, HIV-1 protease, 6.0 nM final concentration, was added to asolution containing inhibitor, 40 μM substrate III and 1.0% Me₂SO inassay buffer: 80 mM MES [2-(N-morpholine)ethane sufonic acid] hydrate,160 mM NaCl, 1.0 mM EDTA (ethylenediaminetetraacetic acid) 0.1%polyethylene glycol (MW 8000) pH 6.2 at 37° C. (total volume, 100 & 1).Polyethylene glycol was used in the assay in place of glycerol since theformer was reported to be a more effective stabilizing agent in theprotease (Jordan, et al., J. Biol. Chem., 1992;267:20028). The finalinhibitor concentrations used were 0 (0.1, 0.2, in some experiments),0.5, 1, 2, 5, 10, 20, 50, and 100 μM. The solution was mixed, incubatedfor 5 minutes and the reaction quenched by addition of trifluoraceticacid, 2% final. The (leu-p-nitro-phe) bond of the substrate is cleavedby the enzyme and substrate and products separated by reverse-phase HPLC(high pressure liquid chromatography). Absorbance was measured at 220nm, peak areas determined, and percentage conversion to product used tocalculate percentage control (=[% conversion (+inhibitor)/% conversion(−inhibitor)]×100).

Cellular Infection Assay

Compounds were tested in lymphocyte derived CEM cells using the XTTcytopathic procedures and were performed at Southern Research Institute(Buckheit, et al., Antiviral Res., 1993;21:247; see also Weislow, etal., J. Nat. Cancer Inst., 1989;81:577). Compound concentrations were0.32, 1, 3.2, 10, 32, and 100 μM. The EC₅₀ represents the concentrationof agent, which reduces HIV cytopathic effects 50% relative to untreatedcontrol. Cellular toxicity of the agents are estimated from the TC₅₀which represents the concentration of the agent which inhibits 50% ofthe viability of uninfected cells.

Table 1 contains the results of the HIV protease assay Ki and theantiviral efficacy (EC₅₀, TC₅₀, TI) screening, where TI is thetherapeutic index (TC₅₀/EC₅₀).

EC₅₀ indicates the concentration of the drug which provide 50%protection against HIV.

TC₅₀ indicates the concentration of the drug which elicits cytotoxicityin 50% of uninfected cells.

Ki means inhibitory constant; it approximately the equilibrium bindingconstant for the binding of the inhibitor to the free enzyme.

TABLE 1 Inhibition of HIV-Protease and Antiviral Efficacy in a CEM CellInfection Assay Inhibition of HIV Antiviral Efficacy Protease Ki EC₅₀TC₅₀ Example (nM) (μM) (μM) TI  1 0.029 0.7  63 90  2 0.083 1    71 71 3 0.96  1.1  66 60  4 0.01  1.1  84 76.4  5 0.17  1.3 113 86.9  6 0.44 1.3 133 102.3  7 0.13  1.3 200 153.8  8 0.35  1.3  67 51.5  9 2    1.4101 72.1 13 0.2  1.5 156 104 14 0.54  1.6 210 131 21 1.6  2.7 320 118.5

Table 1 indicates that the compounds of the present invention have goodto excellent activity toward inhibiting the HIV protease enzyme (Ki's)as well as activity in HIV infected cells, protecting the cells from HIVpathogenicity at μM and sub-μM concentrations.

While the forms of the invention herein disclosed constitute presentlypreferred embodiments, many others are possible. It is not intendedherein to mention all of the possible equivalent forms or ramificationsof the invention. It is understood that the terms used herein are merelydescriptive, rather than limiting, and that various changes may be madewithout departing from the spirit or scope of the invention.

What is claimed is:
 1. A compound of Formula I or its pharmaceuticallyacceptable salts

wherein: R₁ is H, a straight or branched alkyl of 1-6 carbons or acarbocycle of 3-6 carbons; R₂ is H, a straight or branched alkyl of 1-5carbons or a carbocycle of 3-6 carbons; R₃ is H, [C(R₉)₂]_(n)OR,[C(R₉)₂]_(n)N(R)₂, [C(R₉)₂]_(n)N (R₉)COR, [C(R₉)₂]_(n)CO₂R,[C(R₉)₂]_(n)(O)COR, [C(R₉)₂]_(n)CON(R)₂, [C(R₉)₂]_(n)OC(O)N(R)₂,[C(R₉)₂R], [C(R₉)₂]_(n)N(R₉)CON(R)₂, [C(R₉)₂]_(n)N(R₉)CO₂R,[C(R₉)₂]_(n)OSO₂N(R)₂, [C(R₉)₂]_(n)N(R₉)SO₂R, [C(R₉)₂]_(n)N(R₉)SO₂N(R)₂,[C(R₉)₂]_(n)OSO₂R, [C(R₉)₂]_(n)N (R₉)SO₂R, [C(R₉)₂]_(n)SO_(p)R,[C(R₉)₂]_(n)N (R₉)CSN(R)₂, [C(R₉)₂]_(n)N(R₉)C(═NR₉)N(R)₂,[C(R₉)₂]_(n)SO₂N(R)₂, [C(R₉)₂]_(n)C(NR₉)N(R)₂, [C(R₉)₂]_(n)COR,O[C(R₉)₂]_(m)OR, N(R)[C(R₉)₂]_(m)OR, F, Cl, Br, CF₃, CN, or ═O when Aris Het; R₄, R₅, and R₆ are independently H, a straight or branched alkylof 1-6 carbons, a cycloalkyl of 3-6 carbons, [C(R₉)₂]_(n)OR,[C(R₉)₂]_(n)N(R)₂, F, Cl, Br, CN, CF₃, ═O when Ar is Het;[C(R₉)₂]_(n)N(R₉)COR, [C(R₉)₂]_(n)SO_(p)R, [C(R₉) ₂]_(n)R,[C(R₉)₂]_(n)(O)COR, O[C(R₉)₂]_(m)OR, N(R)[C(R₉)₂]_(m)OR,[C(R₉)₂]_(n)N(R₉)CON(R)₂, [C(R₉)2]_(n)(O)CON(R)₂, [C(R₉)₂]_(n)NR₉CO₂R,[C(R₉)₂]_(n)COR [C(R₉)₂]_(n)CO₂R, [C(R₉)₂]_(n)CON(R)₂,[C(R₉)₂]_(n)N(R₉)SO₂R, [C(R₉)₂]_(n)SO₂N(R)₂, [C(R₉)₂]_(n)N(R₉)SO₂OR,[C(R₉) ₂]_(n)OSO₂N(R)₂, [C(R₉)₂]_(n)N(R₉)SO₂N(R)₂,[C(R₉)₂]_(n)C(═NR₉)N(R)₂, [C(R₉)₂]_(n)N(R₉)C(═NR₉)N(R)₂,[C(R₉)₂]_(n)Het; or any 2 of R₁-R₃ or R₄-R₆ may together form a ring of5-6 total atoms which may contain 0-3 heteroatoms; X is NH or NR₈; f isan integer of from 0 to 3; n is an integer of from 0 to 3; m is aninteger of from 2 to 4; p is an integer from 1 to 2; R₇ is a straight orbranched alkyl of 1-6 carbons or a carbocycle of 3-6 carbons; R₈ is astraight or branched alkyl of 1-6 carbons, a carbocycle of 3-6 carbons,(CH₂)_(n)Ph, or a heterocycle of 5-6 atoms having 1-4 heteroatoms or afused heterocycle of from 9-10 atoms having 1-3 heteroatoms alloptionally substituted by F, Cl, Br, OR₉, CN, CO₂R₉, N(R₉)₂, NR₉COR₉,CF₃, or ═O; or an alkyl group bearing an OH, NH₂, CN substituent; or R₁and R₈ may together form a carbocycle; R is independently H, a straightor branched alkyl of 1-6 carbons, (CH₂)_(n)Ph, or a (CH₂)_(n)heterocycleof 5-6 atoms containing 1-4 heteroatoms, all optionally substituted byF, Cl, Br, OR₉, CN, CO₂R₉, N(R₉)₂, NR₉COR₉, CF₃, or ═O; R₉ isindependently H, a straight or branched alkyl of 1-4 carbons, or phenyl;R₁₀ is independently H, a straight or branched alkyl of 1-4 carbons, F,Cl, Br, OR₉ or N(R₉)₂; or R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉ and R₁₀ maybe alkene or alkyne of from 2-6 carbon atoms; Ar₁ and Ar₂ areindependently phenyl; provided that X is NR₈ when R₇ is a carbocycle. 2.A compound according to claim 1 wherein: R₁ is H or a straight orbranched alkyl of from 1 to 4 carbons or a carbocycle of from 3 to 5carbons and; R₂ is H or straight or branched alkyl of from 1 to 3carbons; and R₈ is H or straight or branched alkyl of from 1 to 6carbons.
 3. A compound according to claim 1 wherein: R₁ is H or astraight or branched alkyl of from 1-4 carbons or a carbocycle of 3-5carbons; R₂ is H or a straight or branched alkyl of from 1-4 carbons orcarbocycle of 3-5 carbons; R₃ is H, [C(R₉)₂]_(n)OR, [C(R₉)₂]_(n)N(R)₂,[C(R₉)₂]_(n)N (R₉)COR, [C(R₉)₂]_(n)CO₂R, [C(R₉)_(n)(O)C(O)R,[C(R₉)]_(n)CON(R)₂, [C(R₉)_(n)OC(O)N(R)₂, [C(R₉)]_(2n)N(R₉)CON(R)₂,[C(R₉)₂]_(n)N(R₉)CO₂R, [C(R₉)₂]_(n)OSO₂N(R)₂, [C(R₉)₂]_(n)N(R₉)SO₂OR,[C(R₉)_(2n)N(R₉)SO₂N(R)₂, [C(R₉) ₂]_(n)OSO₂R, [C(R₉)2]_(n)N (R₉)SO₂R,[C(R₉)₂]_(n)SO_(p)R, [C(R₉)₂]_(n)N (R₉)C(S)N(R)₂, [C(R₉)₂]_(n)COR,O[C(R₉)₂]_(m)OR, N(R)[C(R₉)₂]_(m)OR, F, Cl, Br, CF₃, CN, or ═O when Aris Het; R₄, R₅, and R₆ are independently H, a straight or branched alkylof 1-6 carbons, a cycloalkyl of 3-6 carbons, [C(R₉)₂]_(n)OR,[C(H₂)₂]_(n)N(R)₂, F, Cl, Br, CN, CF₃, ═O when Ar is Het;[C(R₉)₂]_(n)N(R₉)COR, [C(R₉)₂]_(n)SO_(n)R, [C(R₉)₂]_(n)N(R₉)C(O)N(R)₂,[C(R₉)₂]_(n)OCON(R)₂, [C(R₉)₂]_(n)NR₉CO₂R, [C(R₉)₂]_(n)COR,[C(R₉)₂]_(n)CO₂R, [C(R₉)₂]_(n)CON(R)₂, [C(R₉)₂]_(n)N (R₉)SO₂R,[C(R₉)₂]_(n)OSO₂N(R)₂ [C(R₉)₂]_(n)N(R₉)SO₂OR, [C(R₉)₂]_(n) OSO₂NR₂,[C(R₉)₂]_(n) Het; or any two of R₁-R₃ or R₄-R₆ may together form a ringof 5-6 total atoms which may contain 0-2 heteroatoms; Ar₁ is phenyl; andAr₂ is 4-hydroxylphenyl or phenyl.
 4. A compound according to claim 1wherein: R₁ is independently H or a straight or branched alkyl of from1-4 carbons or a carbocycle of 3-5 carbon atoms; R₂ is independently Hor a straight or branched alkyl of from 1-4 carbons or a carbocycle of3-5 carbon atoms; R₃ is independently H, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂,(CH₂)_(n)N(R₉)COR, (CH₂)_(n)C(O)N(R)₂, (CH₂)_(n)OCON(R)₂,(CH₂)_(n)N(R₉)C(O)N(R)₂, (CH₂)_(n)N(R₉)CO₂R, (CH₂)_(n)OSO₂N(R)₂,(CH₂)_(n)NR₉SO₂OR, (CH₂)_(n)N(R₉)SO₂N(R)₂, (CH₂)_(n)OSO₂R,(CH₂)_(n)N(R₉)SO₂R, (CH₂)_(n)SO₂R, (CH₂)_(n)N(R₉)C(S)N(R)₂,(CH₂)_(n)COR, O(CH₂)_(m)OR₉, NR(CH₂)_(m)O(R₉), or C(CH₃)₂OR₉; R₄, R₅,and R₆ are independently H, a straight or branched alkyl of 1-6 carbons,a cycloalkyl of 3-6 carbons, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, F, Cl, Br, CN,CF₃, ═O, when Ar is Het; (CH₂)_(n)N(R₉)COR, (CH₂)_(n)N(R₉)C(O)N(R)₂,(CH₂)_(n)OC(O)N(R)₂, (CH₂)_(n)N(R₉)CO₂R, (CH₂)_(n)COR,(CH₂)_(p)C(O)N(R)₂, (CH₂)_(n)N(R₉)SO₂R, (CH₂)_(n)N(R₉)SO₂OR,(CH₂)_(n)OSO₂N(R)₂wherein n is 0-2, or R₄ and R₅ may together form aring of 5-6 total atoms which may contain 0-2 heteroatoms; R is H, astraight or branched alkyl of 1-4 carbons, (CH₂)_(n)Ph, or a heterocycleof 5-6 atoms having 1-4 heteroatoms or a fused heterocycle of from 9-10atoms having 1-3 heteroatoms, all optionally substituted by F, Cl, Br,OR₉, N(R₉)₂, NR₉COR₉, or ═O; Ar₁ is phenyl; and Ar₂ is 4-hydroxyphenylor phenyl.
 5. A compound according to claim 1 wherein: R₃ is H,(CH₂)_(n)OR, (CH₂)_(n)N(R)₂, (CH₂)_(n)N(R₉)COR, (CH₂)_(n)C(O)N(R) ₂,(CH₂)_(n)OC(O)N(R)₂, (CH₂)_(n)N(R₉)C(O)N(R)₂, (CH₂)_(n)N(R₉)CO₂R,(CH₂)_(n)OSO₂N(R)₂, (CH₂)_(n)N(R₉)SO₂OR, (CH₂)_(n)N(R₉)SO₂N(R)₂,(CH₂)_(n)OSO₂R, (CH₂)_(n)N(R₉)SO₂R, (CH₂)_(n)SO₂R, (CH₂)_(n)COR, O(CH₂)_(m)OR, NR(CH₂)_(m)OR, C(CH₃)₂OR₉, F, Cl, Br, CF₃, or ═O which isHet; R₄, R₅, and R₆ are independently H, a straight or branched alkyl of1-6 carbons, a cycloalkyl of 3-6 carbons, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂,F, Cl, Br, ═O, (CF₂)_(n)N(R₉)COR, (CH₂)_(n)N(R₉)C(O)N(R)₂,(CH₂)_(n)OC(O)N(R)₂, (CH₂)_(n)N(R)₉CO₂R, (CH₂)_(n)COR,(CH₂)_(n)C(O)N(R)₂, (CH₂)_(n)N(R)SO₂R, (CH₂)_(n)N(R₉)SO₂OR,(CH₂)_(n)OSO₂N(R)₂, wherein n is 0-2; R₄ and R₅ may together form a ringof 5-6 total atoms, which may contain 0-2 heteroatoms; R₇ isindependently methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl; R₈ is independently H or a straight orbranched alkyl of 1-6 carbons or a carbocycle of 3-6 carbons; R isindependently H, a straight or branched alkyl of 1-4 carbons,(CH₂)_(n)Ph, or a heterocycle of 5-6 atoms having 1-4 heteroatoms or afused heterocycle of from 9-10 atoms having 1-3 heteroatoms, alloptionally substituted by F, Cl, Br, OR₉, N(R₉)₂, NR₉COR₉, or ═O; Ar₁ isphenyl; and Ar₂ is 4-hydroxylphenyl or phenyl.
 6. A compound accordingto claim 1 wherein: R₁ is H, or a straight or branched alkyl of 1-4carbons or a carbocycle of 3-5 carbons; R₂ is H or methyl or a straightor branched alkyl of 1-4 carbons or a carbocycle of 3-4 carbons; R₃ isH, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, (CH₂)_(n)N(R₉)COR, (CH₂)_(n)C(O)N(R) ₂,(CH₂)_(n)OC(O)N(R)₂, (CH₂)_(n)N(R₉)C(O)N(R)₂, (CH₂)_(n)N(R₉)CO₂R,(CH₂)_(n)OSO₂N(R)₂, (CH₂)_(n)N(R₉)SO₂OR, (CH₂)_(n)N(R₉)SO₂N(R) ₂,(CH₂)_(n)OSO₂R, (CH₂)_(n)N(R₉)SO₂R, (CH₂)_(n)SO₂R, (CH₂)_(n)COR,O(CH₂)_(m)O(R₉), NR(CH₂)_(m)OR₉, C(CH₃)₂OR₉, F, Cl, Br, or CF₃; R₄, R₅,and R₆ are independently H, a straight or branched alkyl of 1-6 carbons,a cycloalkyl of 3-6 carbons, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, F, Cl, Br,CF₃, (CH₂)_(p)N(R₉)C(O)R, (CH₂)_(p)N(R₉)C(O)N(R)₂, (CH₂)_(p)OC(O)N(R)₂,(CH₂)_(n)N(R₉)CO₂R, (CH₂)_(n)COR, (CH₂)_(n)CON(R)₂, (CH₂)_(n)N(R₉) SO₂R,(CH₂)_(n)N(R₉)SO₂OR, (CH₂)_(n)OSO₂N(R)₂, (CH₂)_(n) Het wherein n is 0-2;any two of R₄-R₆ may together form a ring of 5-6 total atoms, which maycontain 0-2 heteroatoms; X is NR₈; R is H, a straight or branched alkylof 1-4 carbons, (CH₂)_(n)Ph, or a heterocycle of 5-6 atoms having 1-4heteroatoms or a fused heterocycle of from 9-10 atoms having 1-3heteroatoms, all optionally substituted by F, Cl, Br, OR₉, N(R₉)₂,NR₉COR₉, or ═O; Ar₁ is phenyl; Ar₂ is 4hydroxyphenyl or phenyl; and R₈and R₁ may together form a ring of 2-5 carbons.
 7. A compound accordingto claim 1 wherein: R₁ is H, or straight or branched alkyl of 1-4carbons or a carbocycle of 3-5 carbons; R₂ is H or a straight orbranched alkyl of 1-4 carbons or a carbocycle of 3-5 carbons; R₃ is H,(CH₂)_(n)OR, (CH₂)_(n)N(R)₂, (CH₂)_(n)OC(O)N(R)₂, (CH₂)_(n)N(R₉)C(O)N(R)₂, (CH₂)_(n)N(R₉)CO₂R, (CH₂)_(n)OSO₂N(R)₂,(CH₂)_(n)N(R₉)SO₂OR, (CH₂)_(n)N(R₉)SO₂N(R)₂, (CH₂)_(n)N(R₉)SO₂R,(CH₂)_(n)SO₂R, O (CH₂)_(m)OR₉, NR(CH₂)_(m)OR₉, or C(CH₃)₂OR₉; R₄, R₅,and R₆ are independently H, a straight or branched alkyl of 1-6 carbons,a cycloalkyl of 3-6 carbons, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, F, Cl, Br, ═O,(CH₂)_(n)N(R₉)C(O)R, (CH₂)_(n)N(R₉)C(O)N(R)₂, (CH₂)_(n)OC(O)N(R)₂,(CH₂)_(n)N(R₉)CO₂R, (CH₂)_(n)COR, (CH₂)_(n)C(O)N(R)₂, (CH₂)_(n)N(R₉)SO₂R, (CH₂)_(n)N(R₉)SO₂OR, (CH₂)_(n)OSO₂N(R)₂, wherein n is 0-2; R₄ andR₅ may together form a ring of 5-6 total atoms, which may contain 0-2heteroatoms; R is H, a straight or branched alkyl of 1-4 carbons,(CH₂)_(n)Ph, or a heterocycle of 5-6 atoms having 1-4 heteroatoms or afused heterocycle of from 9-10 atoms having 1-3 heteroatoms, alloptionally substituted by F, Cl, Br, OR₉, N(R₉)₂, N(R₉)COR₉, or ═O; Ar₁is phenyl; and Ar₂ is phenyl or 4-hydroxyphenyl.
 8. A compound accordingto claim 1 wherein: R₁ is independently H, a straight or branched alkylof 1-6 carbons or a carbocycle of 3-6 carbons; R₂ is independently H, ora straight or branched alkyl of 1-6 carbons or a carbocycle of 3-6carbons; R₃ is independently H, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂,(CH₂)_(n)N(R)C(O)R, (CH₂)_(n)C(O)N(R)₂, (CH₂)_(n)OCON(R)₂,(CH₂)_(n)N(R₉)C(O)N(R)₂, (CH₂)_(n)N(R₉)CO₂R, (CH₂)_(n)OSO₂N(R)₂,(CH₂)_(n)N(R₉)SO₂OR, (CH₂)_(n)N(R₉)SO₂N(R)₂, (CH₂)_(n)OSO₂R,(CH₂)_(n)N(R₉)SO₂R, (CH₂)_(n)SO₂R, O(CH₂)_(m)OR, NR(CH₂)_(m)OR,C(CH₃)₂OR₉, or ═O when Ar is Het; R₄, R₅, and R₆ are independently H, astraight or branched alkyl of 1-6 carbons, a cycloalkyl of 3-6 carbons,(CH₂)_(n)OR, (CH₂)_(n)N(R)₂, F, Cl, Br, ═O, when Ar is Het,(CH₂)_(p)N(R₉)COR, (CH₂)_(p)N(R₉)CON(R)₂, (CH₂)_(p)OC(O)N(R)₂,(CH₂)_(n)N(R₉)CO₂R, (CH₂)_(n)COR, (CH₂)_(n)CON(R)₂, (CH₂)_(n)N(R₉) SO₂R,(CH₂)_(n)N(R₉)SO₂OR, (CH₂)_(n)OSO₂N(R)₂, wherein n is 0-2; R₄ and R₅ maytogether form a ring of 5-6 total atoms, which may contain 0-2heteroatoms; R is H, a straight or branched alkyl of 1-4 carbons,(CH₂)_(n)Ph, or a heterocycle of 5-6 atoms having 1-4 heteroatoms or afused heterocycle of from 9-10 atoms having 1-3 heteroatoms, alloptionally substituted by F, Cl, Br, O(R₉), N(R₉)₂, NR₉COR₉, or ═O; Ar₁is phenyl; and Ar₂ is 4-hydroxyphenyl or phenyl.
 9. A compound accordingto claim 1 wherein: R₁ is independently H or straight or branched alkylof 1-4 carbons or a carbocycle of 3-5 carbons; R₂ is independently H orstraight or branched alkyl of 1-4 carbons or a carbocycle of 3-5carbons; R₃ is independently CH₂OH, NH₂, OCH₂CH₂OH, NHCOR, OSO₂N(R)₂,N(R₉)SO₂OR, NR₉SO₂R, or OSO₂R; R₄, R₅, and R₆ are independently H, astraight or branched alkyl of 1-6 carbons, a cycloalkyl of 1-6 carbons,(CH₂)_(n)OR, (CH₂)_(n)N(R)₂, F, Cl, Br, ═O, (CH₂)_(n)N(R₉)C(O)R,(CH₂)_(n)N(R₉)C(O)N(R)₂, (CH₂)_(n)OC(O)N(R)₂, (CH₂)_(p)N(R₉)CO₂R;(CH₂)_(n)COR, (CH₂)_(n)C(O)N(R)₂, (CH₂)_(n)N(R₉) SO₂R,(CH₂)_(n)N(R₉)SO₂OR, (CH₂)_(n)OSO₂N(R)₂, wherein n is 0-2; R₄ and R₅ maytogether form a ring of 5-6 total atoms, which may contain 0-2heteroatoms; R₇ is independently a straight or branched alkyl of 1-6carbons or a carbocycle of 3-6 carbons, R₈ is H; R is independently H, astraight or branched alkyl of 1-4 carbons, (CH₂)_(n)Ph, or a heterocycleof 5-6 atoms having 1-4 heteroatoms or a fused heterocycle of from 9-10atoms having 1-3 heteroatoms and wherein the (R)₂ in N(R)₂ may be aheterocycle having nitrogen, all optionally substituted by F, Cl, Br,OR₉, N(R₉)₂, N(R₉)C(O)R₉, or ═O; Ar₁ and Ar₂ are phenyl.
 10. A compoundaccording to claim 1 wherein: R₁ is H or straight or branched alkyl of1-4 carbons or a carbocycle of 3-5 carbons; R₂ is independently H orstraight or branched alkyl of 1-4 carbons or a carbocycle of 3-5carbons; R₃ is independently H, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂,(CH₂)_(n)N(R₉)C(O)R, (CH₂)_(n)C(O)N(R)₂, (CH₂)_(n)OC(O)N(R)₂,(CH₂)_(n)N(R₉)C(O)N(R), (CH₂)_(n)N(R₉)CO₂R, (CH₂)_(n)OSO₂N(R)₂,(CH₂)_(n)N(R₉)SO₂OR, (CH₂)_(n)N(R₉)SO₂N(R)₂(CH₂)_(n)OSO₂R,(CH₂)_(n)N(R₉)SO₂R, (CH₂)_(n)SO₂R, (CH₂)_(n)N(R₉)C(S)N(R)₂,(CH₂)_(n)COR, O(CH₂)_(m)OR, NR(CH₂)_(m)OR₉, C(CH₃)₂OR₉, F, Cl, Br, or ═Owhen Ar is Het; R₄, R₅ and R₆ are independently H, methyl, ethyl, OH,CH₂OH, CH₂CH₂OH, F, Cl, NH₂; any two R₄-R₆ may form a ring of 5-6 atomshaving from 1-2 heteroatoms; X is NR₈; R is independently H, a straightor branched alkyl of 1-4 carbons, (CH₂)_(n)Ph, or a (CH₂)_(n)heterocycle of 5-6 atoms having 1-4 heteroatoms or a fused heterocycleof from 9-10 atoms having 1-3 heteroatoms or a heterocycle having anitrogen, all optionally substituted by F, Cl, Br, OR′, N(R′)₂,N(R₉)COR₉, or ═O; R₈ is a straight or branched alkyl of 1-4 carbons or acarbocycle of 3-5 carbon atoms; Ar₁ and Ar₂ are phenyl.
 11. A compoundaccording to claim 1 wherein: R₁ is independently H or straight orbranched alkyl of 1-4 carbons or a carbocycle of 3-5 carbon atoms; R₂ isindependently H or branched alkyl of 1-4 carbons or a carbocycle of 3-5carbon atoms; R₃ is independently H, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, or ═Owhen Ar is Het; R₄, R₅, and R₆ are independently H, methyl, OH, CH₂OH,CH₂CH₂OH, NH₂, or F; R₇ is independently H, isopropyl, butyl, sec-butyl,cyclobutyl, cyclopentyl, or cyclohexyl; X is NR₈; R₈ is independently H,ethyl, n-propyl or n-butyl; R is independently H, methyl, ethyl, phenyl,or CH₂Ph and wherein the (R)₂ of N(R)₂ may be a heterocycle having anitrogen; R₁₀ is independently H, F, or CH₃; Ar₁ is phenyl; and Ar₂ isindependently phenyl or 4-hydroxyphenyl.
 12. A compound according toclaim 1 wherein: R₁ is independently H or straight or branched alkyl of1-4 carbons or a carbocycle of 3-5 carbons; R₂ is independently H orstraight or branched alkyl of 1-4 carbons or a carbocycle of 3-5carbons; R₃ is independently H, NH₂, OH, CH₂OR, CH₂N(R)₂, CH₂C(O)N(R)₂,CH₂OSO₂N(R)₂, CH₂NHSO₂OR, CH₂NHSO₂R, CH₂OSO₂R, Cl, Br, or OCH₂CH₂OH; R₄,R₅, and R₆ are independently H, methyl, ethyl, isopropyl, OH, NH₂,CH₂OR, CH₂N(R)₂, ═O when Ar is Het, F, Cl, Br, or CH₂N(R)C(O)R; R₇ isindependently methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, orcyclopentyl; X is NR₈; R₈ is independently H, ethyl, n-propyl orn-butyl; R is independently H, methyl, ethyl, Ph or CH₂Ph; R₁₀ isindependently H, F, or CH₃; and Ar₁ and Ar₂ are phenyl.
 13. A compoundaccording to claim 1 wherein: R₁ is independently H or straight orbranched alkyl of 1-4 carbons or a carbocycle of 3-5 carbon atoms; R₂ isindependently H or straight or branched alkyl of 1-4 carbons or acarbocycle of 3-5 carbon atoms; R₃ is independently H, NH₂, OH, CH₂OR,CH₂N(R)₂, CH₂C(O)N(R)₂, OSO₂N(R)₂, NHSO₂OR, NHSO₂R, OSO₂R, or OCH₂CH₂OH;R₄, R₅, and R₆ are independently H, methyl, ethyl, isopropyl, OH, NH₂,CH₂OR, CH₂N(R)₂, ═O when Ar is Het, F, Cl, Br, or CH₂NRCOR; R₇ isindependently methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, orcyclopentyl; X is NR₈; R₈ is independently H, ethyl, n-propyl orn-butyl; R is independently H, methyl, ethyl, Ph or CH₂Ph, wherein the(R)₂ in N(R)₂ may be a heterocycle containing the nitrogen; R₁₀ isindependently H, F, or CH₃; Ar₁ is phenyl; Ar₂ is 4-hydroxyphenyl orphenyl; and f is an integer of
 2. 14. A compound according to claim 1wherein: R₁ is independently H or straight or branched alkyl of 1-4carbons or a carbocycle of 3-5 carbon atoms; R₂ is independently H orstraight or branched alkyl of 1-4 carbons or a carbocycle of 3-5 carbonatoms; R₃ is independently NH₂, CH₂OH, OCH₂CH₂OH, or CH₂CH₂OH; R₄, R₅,and R₆ are independently H, NH₂, CH₂OH, ═O when Ar is Het, methyl,ethyl, or isopropyl; R₇ is isopropyl; X is NR₈; R₈ is independently H,ethyl, n-propyl or n-butyl; R₁₀ is independently H, F, or CH₃; Ar₁ isphenyl; Ar₂ is phenyl or 4-hydroxyphenyl; and f is an integer of
 2. 15.A compound according to claim 1 wherein: R₁ is independently H orstraight or branched alkyl of 1-4 carbons or a carbocycle of 3-5 carbonatoms; R₂ is independently H or straight or branched alkyl of 1-4carbons or a carbocycle of 3-5 carbon atoms, R₃ is independently H,CH₂OH, NH₂, or ═O; R₄, R₅, and R₆ are independently H, OH, CH₂OH, NH₂,or F; R₇ is independently isopropyl, sec-butyl, isobutyl, orcyclopentyl; X is NR₈; R₈ is independently H, ethyl, n-propyl orn-butyl; R is independently H, methyl, ethyl, Ph, CH₂Ph, and wherein the(R)₂ in N(R)₂ may be a heterocycle having a nitrogen; R₁₀ is H, F, orCH₃; f is an integer of 2; Ar₁ is phenyl and Ar₂ is phenyl or4-hydroxyphenyl.
 16. A pharmaceutical composition for the treatment ofinfection or disease caused by HIV, which comprises an amount of thecompound of claim 1 sufficient to provide an antivirally effectivedosage of the compound of Formula I and a pharmaceutically effectivecarrier.
 17. A pharmaceutical composition for the treatment of infectionor disease caused by HIV, which comprises an amount of the compound ofclaim 1 in the range of about 1 to about 50 mg/kg-day or up to 3 g perday and a pharmaceutically effective carrier.
 18. A method of treatmentof infection or disease caused by HIV, which comprises administering toa subject in need of such treatment a composition of claim
 1. 19. Acompound according to claim 1 and selected from:5-Trifluoromethyl-pyridine-2-sulfonic acid{3-[(4-hydroxy-6-isopropyl-2-oxo-6-phenethyl-5,6-dihydro-2H-pyran-3-yl)-propyl-amino]-phenyl}-amide;5-Trifluoromethyl-pyridine-2-sulfonic acid[3-({4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-phenyl]-amide;5-Trifluoromethyl-pyridine-2-sulfonic acid{3-[ethyl-(4-hydroxy-6-isopropyl-2-oxo-6-phenethyl-5,6-dihydro-2H-pyran-3-yl)-amino]-phenyl]-amide;5-Trifluoromethyl-pyridine-2-sulfonic acid[3-({4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-phenyl]-amide;5-Trifluoromethyl-pyridine-2-sulfonic acid[3-(ethyl-{4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-2-oxo-6-propyl-5,6-dihydro-2H-pyran-3-yl}-amino)-phenyl]-amide;5-Trifluoromethyl-pyridine-2-sulfonic acid[3-(ethyl-{4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-yl}-amino)phenyl]-amide;4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;6-Cyclopentyl-4-hydroxy-6-[2-(3-hydroxy-phenyl)-ethyl]-3-phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;4-Hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;Thiophene-2-sulfonic acid[3-({4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-phenyl]-amide;5-Trifluoromethyl-pyridine-2-sulfonic acid[3-({4-hydroxy-6-[2-(phenyethyl)-6-(n-propyl)-2-oxo-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-phenyl]-amide;5-Trifluoromethyl-pyridine-2-sulfonic acid[3-({6-cyclopentyl-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-2-oxo-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-phenyl] amide;3-(Butyl-phenyl-amino)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;Pyridine-2-sulfonic acid[3-({4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-phenyl]-amide;3-(Butyl-phenyl-amino)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(Butyl-phenyl-amino)-6-cyclopentyl-4-hydroxy-6-[2-(3-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one;5-Trifluoromethyl-pyridine-2-sulfonic acid[3-({6-[2-(4-amino-phenyl)-ethyl]-4-hydroxy-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-phenyl]-amide;3-[(3,4-Dichloro-phenyl)-propyl-amino]-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;4-Hydroxy-3-[(3-hydroxymethyl-phenyl)-propyl-amino]-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;6-[2-(4-Amino-phenyl)-ethyl]-3-diphenyamino-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;3-({4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-yl)-phenyl-amino)-propionitrile;3-Diphenylamino-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;Pyridine-2-sulfonic acid{3-[ethyl-(4-hydroxy-6-isopropyl-2-oxo-6-phenethyl-5,6-dihydro-2H-pyran-3-yl)-amino]-phenyl}-amide;4-Hydroxy-6-isopropyl-6-phenethyl-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;3-({4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-benzoicacid methyl ester;3-[(3,5-Dichloro-phenyl)-propyl-amino]-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;6-[2-(4-Amino-phenyl)-ethyl]-4-hydroxy-6-isopropyl-3-(phenyl-propyl-amino)5,6-dihydro-pyran-2-one;4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-3-(phenyl-propylamino)-5,6-dihydro-pyran-2-one;4-Hydroxy-6-isopropyl-3-(phenyl-propyl-amino)-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;6-Cyclopentyl-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;4-Hydroxy-3-[(3-hydroxymethyl-phenyl)-propyl-amino]-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(Ethyl-phenyl-amino)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;6-Cyclopentyl-3-diphenylamino-4-hydroxy-6-[2-(3-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one;3-(Cyclohexyl-phenyl-amino)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(Cyclopentyl-phenyl-amino)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;Thiophene-2-sulfonic acid{3-[(4-hydroxy-6-isopropyl-2-oxo-6-phenethyl-5,6-dihydro-2H-pyran-3-yl)-propyl-amino]-phenyl}-amide;4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-3-[(4-methoxy-phenyl)-phenyl-amino]-5,6-dihydro-pyran-2-one;4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-methyl-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-3-[(3-hydroxy-phenyl)-phenyl-amino]-6-isopropyl-5,6-dihydro-pyran-2-one;6-Butyl-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;6-Cyclopropyl-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-3-(isopropyl-phenyl-amino)-5,6-dihydro-pyran-2-one;1-Methyl-1H-imidazole-4-sulfonic acid{3-[ethyl-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-amino]-phenyl}-amide;3-(Ethyl-p-tolyl-amino)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;4-Cyano-N-[3-({4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-methyl-2-oxo-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-phenyl]-benzenesulfonamide;4-Hydroxy-3-[(2-hydroxy-ethyl)-phenyl-amino]-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-methyl-3-(propyl-m-tolyl-amino)-5,6-dihydro-pyran-2-one;1-Methyl-1H-imidazole-4-sulfonic acid[3-(ethyl-{4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-2-oxo-6-propyl-5,6-dihydro-2H-pyran-3-yl}-amino)-phenyl]-amide;4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-3-[(3-methyl-butyl)-phenyl-amino]-5,6-dihydro-pyran-2-one;3-(Cyclopropyl-phenyl-amino)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(tert-Butyl-phenyl-amino)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;(S)-3-[(4-Fluoro-phenyl)-isopropyl-amino]-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-[(3-Amino-phenyl)-ethyl-amino]-4-hydroxy-6-isopropyl-6-phenethyl-5,6-dihydro-pyran-2-one;3-(Ethyl-o-tolyl-amino)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(Benzyl-phenyl-amino)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;Dimethyl-sulfamic acid3-({4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-methyl-2-oxo-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-phenylester;[3-(3,4-Dihydro-2H-quinoxalin-1-yl)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-methyl-5,6-dihydro-pyran-2-one;]6-Cyclohexyl-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;6-Cyclopentyl-3-diphenylamino-4-hydroxy-[2-(4-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one;[3-[(3,5-Dichloro-phenyl)-propyl-amino]-4-hydroxy-6-[2-(4-hydroxy-phenyl)ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;]6-(2-Furan-3-yl-ethyl)-4-hydroxy-6-[4-(2-hydroxy-ethoxy)-phenyl]-3-phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;6-Cyclopentyl-3-(ethyl-phenyl-amino)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one;[2-(4-Amino-phenyl)-ethyl]-(ethyl-phenyl-amino)-hydroxy-isopropyl-5,6-dihydro-pyran-2-one;3-[Butyl-(3,5-dichloro-phenyl)-amino]-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-[(3-Chloro-phenyl)-propyl-amino]-4-hydroxy-6-[4-(2-hydroxy-ethoxy)-phenyl]-6-phenethyl-5,6-dihydro-pyran-2-one;Pyridine-2-sulfonic acid{3-[ethyl-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-amino]-phenyl}-amide;6-Cyclopropyl-3-(ethyl-phenyl-amino)-4-hydroxy-[2-(4-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one;4-Hydroxy-6-[4-(2-hydroxy-ethoxy)-phenyl]-6-phenethyl-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-phenethyl-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;6-(2-Cyclopentyl-ethyl)-4-hydroxy-6-[4-(2-hydroxy-ethoxy)-phenyl]-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;6-Ethyl-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-3-(phenyl-propyl-amino)-6-[4-(2-piperazin1-yl-ethoxy)-phenyl]-5,6-dihydropyran-2-one;3-Diphenylamino-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;4-Hydroxy-6-[4-(2-hydroxy-ethoxy)-phenyl]-6-phenyl-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-3-(phenyl-propyl-amino)-6-propyl-5,6-dihydro-pyran-2-one;6-[2-(4-Amino-phenyl)-ethyl]-4-hydroxy-6-phenyl-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;4-Hydroxy-6-(4-methoxymethoxy-phenyl)-6-phenyl-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;Thiophene-2-sulfonic acid{3-[ethyl-(4-hydroxy-6-isopropyl-2-oxo-6-phenethyl-5,6-dihydro-2H-pyran-3-yl)-amino]-phenyl}-amide;6-Cyclopropyl-3-(ethyl-phenyl-amino)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one;6-Cyclopentyl-3-(ethyl-phenyl-amino)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl)-5,6-dihydro-pyran-2-one;3-Diphenlylamino-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-propyl-5,6-dihydro-pyran-2-one;4-Hydroxy-3-[(3-methylsulfanyl-phenyl)-propyl-amino]-6-phenethyl-6-phenyl-5,6-dihydro-pyran-2-one;Dimethyl-sulfamic acid3-({4-hydroxy-6-[4-(2-hydroxy-ethoxy)-phenyl]-2-oxo-6phenethyl-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-phenylester;3-(Butyl-phenyl-amino)-4-hydroxy-6-phenethyl-6-phenyl-5,6-dihydro-pyran-2-one;3-Diphenylamino-4-hydroxy-6-phenethyl-6-phenyl-5,6-dihydro-pyran-2-one;1-Methyl-1H-imidazole-4-sulfonic acid[3-({4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-methyl-2-oxo-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-phenyl]-amide;4-Hydroxy-6-phenethyl-6-phenyl-3-(propyl-m-tolyl-amino)-5,6-dihydro-pyran-2-one;4-Hydroxy-6-phenethyl-6-phenyl-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;4-Hydroxy-3-[(3-hydroxymethyl-phenyl)-propyl-amino]-6-[2-(4-hydroxy-phenyl)-ethyl]-6-methyl-5,6-dihydro-pyran-2-one;4-Hydroxy-6-pentyl-6-phenyl-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;4-Hydroxy-6-[4-(2-hydroxy-ethoxy)-phenyl]-3-[(3-hydroxy-phenyl)-propyl-amino]-6-phenethyl-5,6-dihydro-pyran-2-one;3-[(4-Hydroxy-2-oxo-6-phenethyl-6-phenyl-5,6-dihydro-2H-pyran-3-yl)-propyl-amino]-benzoicacid methyl ester;N-(3-{2-[4-Hydroxy-6-oxo-2-phenyl-5-(phenyl-propyl-amino)-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-acetamide;4-Hydroxy-3-[(3-hydroxymethyl-phenyl)-propyl-amino]-6-phenethyl-6-phenyl-5,6-dihydro-pyran-2-one;4-Hydroxy-6-[4-(2-hydroxy-ethoxy)-phenyl]-3-(phenyl-propyl-amino)-6-[2-(tetrahydro-furan-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;5-({4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-isophthalicacid dimethyl ester;4-Hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-3-[(3-hydroxymethyl-phenyl)-phenyl-amino]-6-isopropyl-5,6-dihydro-pyran-2-one;3-Diphenylamino-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-methyl-5,6-dihydro-pyran-2-one;N-(4-{2-[4-Hydroxy-6-oxo-2-phenyl-5-(phenyl-propyl-amino)-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-acetamide;4-Hydroxy-3-{[3-(2-hydroxy-ethoxy)-phenyl]-propyl-amino}-6-phenethyl-6-phenyl-5,6-dihydro-pyran-2-one;3-(Ethyl-phenyl-amino)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-methyl-5,6-dihydro-pyran-2-one;3-(Ethyl-phenyl-amino)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-propyl-5,6-dihydro-pyran-2-one;(R)-4-Hydroxy-6-isopropyl-6-phenethyl-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;4-Hydroxy-6-phenethyl-6-phenyl-3-o-tolylamino-5,6-dihydro-pyran-2-one;4-Hydroxy-3-(2-isopropyl-phenylamino)-6-phenethyl-6-phenyl-5,6-dihydro-pyran-2-one;4-Hydroxy-3-(2-isopropyl-phenylamino)-6,6-diphenyl-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-5-methyl-phenylamino)-4-hydroxy-6-phenethyl-6-phenyl-5,6-dihydro-pyran-2-one;3-(2-tent-Butyl-5-methyl-phenylamino)-4-hydroxy-6,6-diphenyl-5,6-dihydro-pyran-2-one;3-(Ethyl-phenyl-amino)-4-hydroxy-6-phenethyl-6-phenyl-5,6-dihydro-pyran-2-one;4-Hydroxy-3-(isopropyl-phenyl-amino)-6-phenethyl-6-phenyl-5,6-dihydro-pyran-2-one;4-Hydroxy-3-(methyl-phenyl-amino)-6-phenethyl-6-phenyl-5,6-dihydro-pyran-2-one;4-Hydroxy-3-(isobutyl-phenyl-amino)-6-phenethyl-6-phenyl-5,6-dihydro-pyran-2-one;4-Hydroxy-6-phenethyl-6-phenyl-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;3-(Allyl-phenyl-amino)-4-hydroxy-6-phenethyl-6-phenyl-5,6-dihydro-pyran-2-one;3-(Benzyl-phenyl-amino)-4-hydroxy-6-phenethyl-6-phenyl-5,6-dihydro-pyran-2-one;3-(Cyclopropylmethyl-phenyl-amino)-4-hydroxy-6-phenethyl-6-phenyl-5,6-dihydro-pyran-2-one;4-Hydroxy-6-[4-(2-hydroxy-ethoxy)-phenyl]-6-methyl-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;4-Hydroxy-6-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethyl]-6-methyl-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;4-Hydroxy-3-[(2-methoxy-phenyl)-propyl-amino]-6-phenethyl-6-phenyl-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-phenylamino)-4-hydroxy-6-phenethyl-6-phenyl-5,6-dihydro-pyran-2-one;4-Hydroxy-3-[(2-hydroxy-ethyl)-phenyl-amino]-6-phenethyl-6-phenyl-5,6-dihydro-pyran-2-one;[(4-Hydroxy-2-oxo-6-phenethyl-6-phenyl-5,6-dihydro-2H-pyran-3-yl)-phenyl-amino]-aceticacid ethyl ester;3-[(3-Ethyl-phenyl)-propyl-amino]-4-hydroxy-6-phenethyl-6-phenyl-5,6-dihydro-pyran-2-one;4-Hydroxy-3-{[3-(2-hydroxy-ethoxy)-phenyl]-propyl-amino}-6-[2-(4-hydroxy-phenyl)-ethyl]-6-methyl-5,6-dihydro-pyran-2-one;3-({4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-methyl-2-oxo-5,6-dihydro-2H-pyran3-yl}-propyl-amino)-benzoic acid methyl ester;[3-({4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-methyl-2-oxo-5,6-dihydro-2H-pyran-3-yl}-propyl-amino)-phenyl]-carbamicacid tert-butyl ester;4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-3-[(3-hydroxy-phenyl)-propyl-amino]-6-methyl-5,6-dihydro-pyran-2-one;4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-methyl-3-(methyl-phenyl-amino)-5,6-dihydro-pyran-2-one;3-[(3-Amino-phenyl)-ethyl-amino]-4-hydroxy-6-phenethyl-6-propyl-5,6-dihydro-pyran-2-one;3-[(3-Amino-phenyl)-ethyl-amino]-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-Diphenylamino-4-hydroxy-6-isopropyl-6-phenethyl-5,6-dihydro-pyran-2-one;3-(Ethyl-phenyl-amino)-4-hydroxy-6-isopropyl-6-phenethyl-5,6-dihydro-pyran-2-one;6-(3-Amino-propyl-phenyl)-4-hydroxy-6-methyl-3-(phenyl-propyl-amino)-5,6-dihydro-pyran-2-one;and6-Cyclopentyl-4-hydroxy-3-[(3-hydroxymethyl-phenyl)-propyl-amino]-6-[2-(3-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one.20. A compound according to claim 1 and selected from:4-Hydroxy-3-(2-isopropylphenylamino)-6-phenethyl-6-phenyl-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-5-methyl)-phenylamino)-4-hydroxy-6-phenethyl-6-phenyl-5,6-dihydro-pyran-2-one;and3-(2-tert-Butyl-4-hydroxymethyl-5-methyl)-phenylamino)-4-hydroxy-6-phenethyl-6-phenyl-5,6-dihydro-pyran-2-one.